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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evaluation of Association of <italic>HNF1B</italic> Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies</title><author><name sortKey="Elliott, Katherine S" sort="Elliott, Katherine S" uniqKey="Elliott K" first="Katherine S." last="Elliott">Katherine S. Elliott</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zeggini, Eleftheria" sort="Zeggini, Eleftheria" uniqKey="Zeggini E" first="Eleftheria" last="Zeggini">Eleftheria Zeggini</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Applied Statistical Genetics, Wellcome Trust Sanger Institute, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccarthy, Mark I" sort="Mccarthy, Mark I" uniqKey="Mccarthy M" first="Mark I." last="Mccarthy">Mark I. Mccarthy</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gudmundsson, Julius" sort="Gudmundsson, Julius" uniqKey="Gudmundsson J" first="Julius" last="Gudmundsson">Julius Gudmundsson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sulem, Patrick" sort="Sulem, Patrick" uniqKey="Sulem P" first="Patrick" last="Sulem">Patrick Sulem</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stacey, Simon N" sort="Stacey, Simon N" uniqKey="Stacey S" first="Simon N." last="Stacey">Simon N. Stacey</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thorlacius, Steinunn" sort="Thorlacius, Steinunn" uniqKey="Thorlacius S" first="Steinunn" last="Thorlacius">Steinunn Thorlacius</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amundadottir, Laufey" sort="Amundadottir, Laufey" uniqKey="Amundadottir L" first="Laufey" last="Amundadottir">Laufey Amundadottir</name><affiliation><nlm:aff id="aff5"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gronberg, Henrik" sort="Gronberg, Henrik" uniqKey="Gronberg H" first="Henrik" last="Grönberg">Henrik Grönberg</name><affiliation><nlm:aff id="aff6"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Xu, Jianfeng" sort="Xu, Jianfeng" uniqKey="Xu J" first="Jianfeng" last="Xu">Jianfeng Xu</name><affiliation><nlm:aff id="aff7"><addr-line>Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gaborieau, Valerie" sort="Gaborieau, Valerie" uniqKey="Gaborieau V" first="Valerie" last="Gaborieau">Valerie Gaborieau</name><affiliation><nlm:aff id="aff9"><addr-line>Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eeles, Rosalind A" sort="Eeles, Rosalind A" uniqKey="Eeles R" first="Rosalind A." last="Eeles">Rosalind A. Eeles</name><affiliation><nlm:aff id="aff10"><addr-line>Oncogenetics Team, The Institute of Cancer Research, Sutton, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neal, David E" sort="Neal, David E" uniqKey="Neal D" first="David E." last="Neal">David E. Neal</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Donovan, Jenny L" sort="Donovan, Jenny L" uniqKey="Donovan J" first="Jenny L." last="Donovan">Jenny L. Donovan</name><affiliation><nlm:aff id="aff12"><addr-line>Department of Social Medicine, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamdy, Freddie C" sort="Hamdy, Freddie C" uniqKey="Hamdy F" first="Freddie C." last="Hamdy">Freddie C. Hamdy</name><affiliation><nlm:aff id="aff13"><addr-line>Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muir, Kenneth" sort="Muir, Kenneth" uniqKey="Muir K" first="Kenneth" last="Muir">Kenneth Muir</name><affiliation><nlm:aff id="aff14"><addr-line>Health Sciences Research Institute, University of Warwick, Coventry, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="aff15"><addr-line>Framingham Study, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spitz, Margaret R" sort="Spitz, Margaret R" uniqKey="Spitz M" first="Margaret R." last="Spitz">Margaret R. Spitz</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zanke, Brent" sort="Zanke, Brent" uniqKey="Zanke B" first="Brent" last="Zanke">Brent Zanke</name><affiliation><nlm:aff id="aff17"><addr-line>Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carvajal Carmona, Luis" sort="Carvajal Carmona, Luis" uniqKey="Carvajal Carmona L" first="Luis" last="Carvajal-Carmona">Luis Carvajal-Carmona</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Kevin M" sort="Brown, Kevin M" uniqKey="Brown K" first="Kevin M." last="Brown">Kevin M. Brown</name><affiliation><nlm:aff id="aff19"><addr-line>Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hayward, Nicholas K" sort="Hayward, Nicholas K" uniqKey="Hayward N" first="Nicholas K." last="Hayward">Nicholas K. Hayward</name><affiliation><nlm:aff id="aff20"><addr-line>Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Macgregor, Stuart" sort="Macgregor, Stuart" uniqKey="Macgregor S" first="Stuart" last="Macgregor">Stuart Macgregor</name><affiliation><nlm:aff id="aff20"><addr-line>Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tomlinson, Ian P M" sort="Tomlinson, Ian P M" uniqKey="Tomlinson I" first="Ian P. M." last="Tomlinson">Ian P. M. Tomlinson</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lemire, Mathieu" sort="Lemire, Mathieu" uniqKey="Lemire M" first="Mathieu" last="Lemire">Mathieu Lemire</name><affiliation><nlm:aff id="aff17"><addr-line>Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amos, Christopher I" sort="Amos, Christopher I" uniqKey="Amos C" first="Christopher I." last="Amos">Christopher I. Amos</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Murabito, Joanne M" sort="Murabito, Joanne M" uniqKey="Murabito J" first="Joanne M." last="Murabito">Joanne M. Murabito</name><affiliation><nlm:aff id="aff21"><addr-line>Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Isaacs, William B" sort="Isaacs, William B" uniqKey="Isaacs W" first="William B." last="Isaacs">William B. Isaacs</name><affiliation><nlm:aff id="aff22"><addr-line>The Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="aff23"><addr-line>Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brennan, Paul" sort="Brennan, Paul" uniqKey="Brennan P" first="Paul" last="Brennan">Paul Brennan</name><affiliation><nlm:aff id="aff9"><addr-line>Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Barkardottir, Rosa B" sort="Barkardottir, Rosa B" uniqKey="Barkardottir R" first="Rosa B." last="Barkardottir">Rosa B. Barkardottir</name><affiliation><nlm:aff id="aff24"><addr-line>Department of Pathology, Landspitali-University Hospital of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Faculty of Medicine, University of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gudbjartsson, Daniel F" sort="Gudbjartsson, Daniel F" uniqKey="Gudbjartsson D" first="Daniel F." last="Gudbjartsson">Daniel F. Gudbjartsson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rafnar, Thorunn" sort="Rafnar, Thorunn" uniqKey="Rafnar T" first="Thorunn" last="Rafnar">Thorunn Rafnar</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="aff26"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff5"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name><affiliation><nlm:aff id="aff27"><addr-line>Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff28"><addr-line>Center for Genetic Epidemiology and Modelling, Tufts University School of Medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20526366</idno><idno type="pmc">2878330</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878330</idno><idno type="RBID">PMC:2878330</idno><idno type="doi">10.1371/journal.pone.0010858</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">002B85</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002B85</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Evaluation of Association of <italic>HNF1B</italic> Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies</title><author><name sortKey="Elliott, Katherine S" sort="Elliott, Katherine S" uniqKey="Elliott K" first="Katherine S." last="Elliott">Katherine S. Elliott</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zeggini, Eleftheria" sort="Zeggini, Eleftheria" uniqKey="Zeggini E" first="Eleftheria" last="Zeggini">Eleftheria Zeggini</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Applied Statistical Genetics, Wellcome Trust Sanger Institute, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccarthy, Mark I" sort="Mccarthy, Mark I" uniqKey="Mccarthy M" first="Mark I." last="Mccarthy">Mark I. Mccarthy</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gudmundsson, Julius" sort="Gudmundsson, Julius" uniqKey="Gudmundsson J" first="Julius" last="Gudmundsson">Julius Gudmundsson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sulem, Patrick" sort="Sulem, Patrick" uniqKey="Sulem P" first="Patrick" last="Sulem">Patrick Sulem</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stacey, Simon N" sort="Stacey, Simon N" uniqKey="Stacey S" first="Simon N." last="Stacey">Simon N. Stacey</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thorlacius, Steinunn" sort="Thorlacius, Steinunn" uniqKey="Thorlacius S" first="Steinunn" last="Thorlacius">Steinunn Thorlacius</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amundadottir, Laufey" sort="Amundadottir, Laufey" uniqKey="Amundadottir L" first="Laufey" last="Amundadottir">Laufey Amundadottir</name><affiliation><nlm:aff id="aff5"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gronberg, Henrik" sort="Gronberg, Henrik" uniqKey="Gronberg H" first="Henrik" last="Grönberg">Henrik Grönberg</name><affiliation><nlm:aff id="aff6"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Xu, Jianfeng" sort="Xu, Jianfeng" uniqKey="Xu J" first="Jianfeng" last="Xu">Jianfeng Xu</name><affiliation><nlm:aff id="aff7"><addr-line>Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gaborieau, Valerie" sort="Gaborieau, Valerie" uniqKey="Gaborieau V" first="Valerie" last="Gaborieau">Valerie Gaborieau</name><affiliation><nlm:aff id="aff9"><addr-line>Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eeles, Rosalind A" sort="Eeles, Rosalind A" uniqKey="Eeles R" first="Rosalind A." last="Eeles">Rosalind A. Eeles</name><affiliation><nlm:aff id="aff10"><addr-line>Oncogenetics Team, The Institute of Cancer Research, Sutton, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neal, David E" sort="Neal, David E" uniqKey="Neal D" first="David E." last="Neal">David E. Neal</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Donovan, Jenny L" sort="Donovan, Jenny L" uniqKey="Donovan J" first="Jenny L." last="Donovan">Jenny L. Donovan</name><affiliation><nlm:aff id="aff12"><addr-line>Department of Social Medicine, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamdy, Freddie C" sort="Hamdy, Freddie C" uniqKey="Hamdy F" first="Freddie C." last="Hamdy">Freddie C. Hamdy</name><affiliation><nlm:aff id="aff13"><addr-line>Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muir, Kenneth" sort="Muir, Kenneth" uniqKey="Muir K" first="Kenneth" last="Muir">Kenneth Muir</name><affiliation><nlm:aff id="aff14"><addr-line>Health Sciences Research Institute, University of Warwick, Coventry, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hwang, Shih Jen" sort="Hwang, Shih Jen" uniqKey="Hwang S" first="Shih-Jen" last="Hwang">Shih-Jen Hwang</name><affiliation><nlm:aff id="aff15"><addr-line>Framingham Study, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spitz, Margaret R" sort="Spitz, Margaret R" uniqKey="Spitz M" first="Margaret R." last="Spitz">Margaret R. Spitz</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zanke, Brent" sort="Zanke, Brent" uniqKey="Zanke B" first="Brent" last="Zanke">Brent Zanke</name><affiliation><nlm:aff id="aff17"><addr-line>Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carvajal Carmona, Luis" sort="Carvajal Carmona, Luis" uniqKey="Carvajal Carmona L" first="Luis" last="Carvajal-Carmona">Luis Carvajal-Carmona</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Kevin M" sort="Brown, Kevin M" uniqKey="Brown K" first="Kevin M." last="Brown">Kevin M. Brown</name><affiliation><nlm:aff id="aff19"><addr-line>Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hayward, Nicholas K" sort="Hayward, Nicholas K" uniqKey="Hayward N" first="Nicholas K." last="Hayward">Nicholas K. Hayward</name><affiliation><nlm:aff id="aff20"><addr-line>Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Macgregor, Stuart" sort="Macgregor, Stuart" uniqKey="Macgregor S" first="Stuart" last="Macgregor">Stuart Macgregor</name><affiliation><nlm:aff id="aff20"><addr-line>Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tomlinson, Ian P M" sort="Tomlinson, Ian P M" uniqKey="Tomlinson I" first="Ian P. M." last="Tomlinson">Ian P. M. Tomlinson</name><affiliation><nlm:aff id="aff1"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lemire, Mathieu" sort="Lemire, Mathieu" uniqKey="Lemire M" first="Mathieu" last="Lemire">Mathieu Lemire</name><affiliation><nlm:aff id="aff17"><addr-line>Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amos, Christopher I" sort="Amos, Christopher I" uniqKey="Amos C" first="Christopher I." last="Amos">Christopher I. Amos</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Murabito, Joanne M" sort="Murabito, Joanne M" uniqKey="Murabito J" first="Joanne M." last="Murabito">Joanne M. Murabito</name><affiliation><nlm:aff id="aff21"><addr-line>Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Isaacs, William B" sort="Isaacs, William B" uniqKey="Isaacs W" first="William B." last="Isaacs">William B. Isaacs</name><affiliation><nlm:aff id="aff22"><addr-line>The Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="aff23"><addr-line>Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brennan, Paul" sort="Brennan, Paul" uniqKey="Brennan P" first="Paul" last="Brennan">Paul Brennan</name><affiliation><nlm:aff id="aff9"><addr-line>Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Barkardottir, Rosa B" sort="Barkardottir, Rosa B" uniqKey="Barkardottir R" first="Rosa B." last="Barkardottir">Rosa B. Barkardottir</name><affiliation><nlm:aff id="aff24"><addr-line>Department of Pathology, Landspitali-University Hospital of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Faculty of Medicine, University of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gudbjartsson, Daniel F" sort="Gudbjartsson, Daniel F" uniqKey="Gudbjartsson D" first="Daniel F." last="Gudbjartsson">Daniel F. Gudbjartsson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rafnar, Thorunn" sort="Rafnar, Thorunn" uniqKey="Rafnar T" first="Thorunn" last="Rafnar">Thorunn Rafnar</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="aff26"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff5"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name><affiliation><nlm:aff id="aff4"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name><affiliation><nlm:aff id="aff27"><addr-line>Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff28"><addr-line>Center for Genetic Epidemiology and Modelling, Tufts University School of Medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Genome-wide association studies have found type 2 diabetes-associated variants in the <italic>HNF1B</italic> gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.</p></sec><sec><title>Methodology/Principal Findings</title><p>In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of <italic>HNF1B</italic>, rs4430796 and rs7501939, which are in linkage disequilibrium (r<sup>2</sup> = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10<sup>−15</sup> for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10<sup>−15</sup> for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association.</p></sec><sec><title>Conclusions/Significance</title><p>The examined <italic>HNF1B</italic> variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Inoue, M" uniqKey="Inoue M">M Inoue</name></author><author><name sortKey="Iwasaki, M" uniqKey="Iwasaki M">M Iwasaki</name></author><author><name sortKey="Otani, T" uniqKey="Otani T">T Otani</name></author><author><name sortKey="Sasazuki, S" uniqKey="Sasazuki S">S Sasazuki</name></author><author><name sortKey="Noda, M" uniqKey="Noda M">M Noda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stattin, P" uniqKey="Stattin P">P Stattin</name></author><author><name sortKey="Bjor, O" uniqKey="Bjor O">O 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Fuchs</name></author><author><name sortKey="Kraft, P" uniqKey="Kraft P">P Kraft</name></author><author><name sortKey="Stolzenberg Solomon, Rz" uniqKey="Stolzenberg Solomon R">RZ Stolzenberg-Solomon</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20526366</article-id><article-id pub-id-type="pmc">2878330</article-id><article-id pub-id-type="publisher-id">10-PONE-RA-17772</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0010858</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Genetics and Genomics/Cancer Genetics</subject><subject>Genetics and Genomics/Comparative Genomics</subject><subject>Genetics and Genomics/Complex Traits</subject><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Diabetes and Endocrinology/Type 2 Diabetes</subject><subject>Oncology/Multiple Endocrine Disorders and Neoplasias</subject><subject>Diabetes and Endocrinology/Type 2 Diabetes</subject><subject>Genetics and Genomics/Cancer Genetics</subject><subject>Genetics and Genomics/Comparative Genomics</subject><subject>Genetics and Genomics/Complex Traits</subject><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Oncology/Multiple Endocrine Disorders and Neoplasias</subject></subj-group></article-categories><title-group><article-title>Evaluation of Association of <italic>HNF1B</italic> Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies</article-title><alt-title alt-title-type="running-head">HNF1B Variants and Cancer Risk</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Elliott</surname><given-names>Katherine S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zeggini</surname><given-names>Eleftheria</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>McCarthy</surname><given-names>Mark I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gudmundsson</surname><given-names>Julius</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sulem</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stacey</surname><given-names>Simon N.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thorlacius</surname><given-names>Steinunn</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Amundadottir</surname><given-names>Laufey</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Grönberg</surname><given-names>Henrik</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Jianfeng</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gaborieau</surname><given-names>Valerie</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eeles</surname><given-names>Rosalind A.</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neal</surname><given-names>David E.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Donovan</surname><given-names>Jenny L.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hamdy</surname><given-names>Freddie C.</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Muir</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hwang</surname><given-names>Shih-Jen</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Spitz</surname><given-names>Margaret R.</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zanke</surname><given-names>Brent</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Carvajal-Carmona</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Kevin M.</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><collab>Australian Melanoma Family Study Investigators</collab><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hayward</surname><given-names>Nicholas K.</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Macgregor</surname><given-names>Stuart</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tomlinson</surname><given-names>Ian P. M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lemire</surname><given-names>Mathieu</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Amos</surname><given-names>Christopher I.</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Murabito</surname><given-names>Joanne M.</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Isaacs</surname><given-names>William B.</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Douglas F.</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brennan</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><collab>The PanScan Consortium</collab><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author"><name><surname>Barkardottir</surname><given-names>Rosa B.</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gudbjartsson</surname><given-names>Daniel F.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rafnar</surname><given-names>Thorunn</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hunter</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chanock</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stefansson</surname><given-names>Kari</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ioannidis</surname><given-names>John P. A.</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref><xref ref-type="aff" rid="aff28"><sup>28</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Applied Statistical Genetics, Wellcome Trust Sanger Institute, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff4"><label>4</label><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Oncogenetics Team, The Institute of Cancer Research, Sutton, United Kingdom</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Department of Social Medicine, University of Bristol, Bristol, United Kingdom</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Health Sciences Research Institute, University of Warwick, Coventry, United Kingdom</addr-line></aff><aff id="aff15"><label>15</label><addr-line>Framingham Study, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America</addr-line></aff><aff id="aff16"><label>16</label><addr-line>Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, United States of America</addr-line></aff><aff id="aff17"><label>17</label><addr-line>Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada</addr-line></aff><aff id="aff18"><label>18</label><addr-line>Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada</addr-line></aff><aff id="aff19"><label>19</label><addr-line>Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America</addr-line></aff><aff id="aff20"><label>20</label><addr-line>Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland, Australia</addr-line></aff><aff id="aff21"><label>21</label><addr-line>Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff22"><label>22</label><addr-line>The Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America</addr-line></aff><aff id="aff23"><label>23</label><addr-line>Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff24"><label>24</label><addr-line>Department of Pathology, Landspitali-University Hospital of Iceland, Reykjavik, Iceland</addr-line></aff><aff id="aff25"><label>25</label><addr-line>Faculty of Medicine, University of Iceland, Reykjavik, Iceland</addr-line></aff><aff id="aff26"><label>26</label><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff27"><label>27</label><addr-line>Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece</addr-line></aff><aff id="aff28"><label>28</label><addr-line>Center for Genetic Epidemiology and Modelling, Tufts University School of Medicine, Boston, Massachusetts, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Kronenberg</surname><given-names>Florian</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Innsbruck Medical University, Austria</aff><author-notes><corresp id="cor1">* E-mail: <email>jioannid@cc.uoi.gr</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: KSE EZ MIM JPAI. Analyzed the data: KSE JPAI. Contributed reagents/materials/analysis tools: KSE JG PS SNS ST LTA HG JX VG RAE DEN JLD FCH KM SJH MRS BZ LCC KMB AMFSI NKH SM IPT ML CIA JMM WBI DFE PB PC RB DFG TR DJH SJC KS. Wrote the paper: KSE EZ MIM JG JPAI.</p></fn><fn id="fn1" fn-type="other"><label>¤</label><p>See acknowledgments for author list.</p></fn></author-notes><pub-date pub-type="collection"><year>2010</year></pub-date><pub-date pub-type="epub"><day>28</day><month>5</month><year>2010</year></pub-date><volume>5</volume><issue>5</issue><elocation-id>e10858</elocation-id><history><date date-type="received"><day>8</day><month>4</month><year>2010</year></date><date date-type="accepted"><day>28</day><month>4</month><year>2010</year></date></history><permissions><copyright-statement>Elliott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement></permissions><abstract><sec><title>Background</title><p>Genome-wide association studies have found type 2 diabetes-associated variants in the <italic>HNF1B</italic> gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.</p></sec><sec><title>Methodology/Principal Findings</title><p>In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of <italic>HNF1B</italic>, rs4430796 and rs7501939, which are in linkage disequilibrium (r<sup>2</sup> = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10<sup>−15</sup> for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10<sup>−15</sup> for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association.</p></sec><sec><title>Conclusions/Significance</title><p>The examined <italic>HNF1B</italic> variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.</p></sec></abstract><counts><page-count count="8"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>A large number of epidemiological studies have suggested correlations between type 2 diabetes (T2D) and various cancers<xref ref-type="bibr" rid="pone.0010858-Inoue1">[1]</xref>, <xref ref-type="bibr" rid="pone.0010858-Stattin1">[2]</xref>, <xref ref-type="bibr" rid="pone.0010858-Rousseau1">[3]</xref>. Most evidence suggests an inverse correlation between T2D and prostate cancer<xref ref-type="bibr" rid="pone.0010858-Kasper1">[4]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gong1">[5]</xref>, <xref ref-type="bibr" rid="pone.0010858-Calton1">[6]</xref> although not all studies agree on this<xref ref-type="bibr" rid="pone.0010858-Will1">[7]</xref>. Several studies also suggest positive correlations between other cancers and T2D<xref ref-type="bibr" rid="pone.0010858-Inoue1">[1]</xref>, <xref ref-type="bibr" rid="pone.0010858-Stattin1">[2]</xref>, <xref ref-type="bibr" rid="pone.0010858-Rousseau1">[3]</xref>. It is unclear whether these correlations, if true, represent casual relationships and whether they may also reflect some shared genetic background. Recently, with the advent of genome-wide association studies (GWAS), a large number of genetic variants have been identified that confer susceptibility to T2D or specific types of cancer<xref ref-type="bibr" rid="pone.0010858-Manolio1">[8]</xref>. An interesting observation has been that specific variants in the <italic>HNF1B</italic> gene (formerly <italic>TCF2</italic>) have been demonstrated to be associated both with the risk of prostate cancer<xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, <xref ref-type="bibr" rid="pone.0010858-Sun1">[10]</xref>, <xref ref-type="bibr" rid="pone.0010858-Thomas1">[11]</xref> and the risk of T2D<xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, <xref ref-type="bibr" rid="pone.0010858-Winckler1">[12]</xref> with the effects being in the opposite direction for these two phenotypes.</p><p><italic>HNF1B</italic> was previously known to be mutated in individuals with maturity-onset diabetes of the young type 5 (MODY 5)<xref ref-type="bibr" rid="pone.0010858-Horikawa1">[13]</xref>, but a biological explanation of the impact of the identified common variation on T2D and prostate cancer risk remains elusive. The identified genetic effects are small in magnitude even for prostate cancer and T2D, representing odds ratios [ORs] per allele in the range of 1.2 <xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, <xref ref-type="bibr" rid="pone.0010858-Thomas1">[11]</xref> and 0.9 <xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, <xref ref-type="bibr" rid="pone.0010858-Winckler1">[12]</xref>, respectively. Therefore, small effects for other cancer types would not be readily detectable, unless very large studies were performed or data were combined from several studies.</p><p>A definitive answer on whether <italic>HNF1B</italic> variants modulate also the risk of other malignancies, or show specificity for prostate cancer, requires large sample sizes. Here we present the results of a large collaborative meta-analysis of <italic>HNF1B</italic>, rs4430796 and rs7501939, which have the most consistent associations with both prostate cancer and T2D. Relevant data were collected on the two variants from GWAS on cancer phenotypes in Caucasian populations in order to examine whether they have an effect on cancer risk in general, on few specific cancers, or only on prostate cancer.</p></sec><sec id="s2"><title>Results</title><sec id="s2a"><title>Database of contributed information</title><p>All the originally contacted investigators of cancer-related GWA studies agreed to participate in this collaborative analysis, with the exception of the investigators of 3 GWA studies <xref ref-type="bibr" rid="pone.0010858-Tenesa1">[14]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gold1">[15]</xref>, <xref ref-type="bibr" rid="pone.0010858-Maris1">[16]</xref> (1 on breast cancer, 1 on colorectal cancer and 1 on neuroblastoma), 1 of which had no data on the requested variants, as they had used a Affymetrix platform<xref ref-type="bibr" rid="pone.0010858-Gold1">[15]</xref>. Investigators who agreed to participate in the collaborative analysis contributed data on 13 datasets for rs4430796 and 19 datasets for rs7501939 <xref ref-type="bibr" rid="pone.0010858-Thomas1">[11]</xref>, <xref ref-type="bibr" rid="pone.0010858-Cust1">[17]</xref>, <xref ref-type="bibr" rid="pone.0010858-Eeles1">[18]</xref>, <xref ref-type="bibr" rid="pone.0010858-Petersen1">[19]</xref>, <xref ref-type="bibr" rid="pone.0010858-Brennan1">[20]</xref>, <xref ref-type="bibr" rid="pone.0010858-Hung1">[21]</xref>, <xref ref-type="bibr" rid="pone.0010858-Amos1">[22]</xref>, <xref ref-type="bibr" rid="pone.0010858-Zanke1">[23]</xref>, <xref ref-type="bibr" rid="pone.0010858-Brown1">[24]</xref>, <xref ref-type="bibr" rid="pone.0010858-Yeager1">[25]</xref>, <xref ref-type="bibr" rid="pone.0010858-Duggan1">[26]</xref>, <xref ref-type="bibr" rid="pone.0010858-Tomlinson1">[27]</xref>, <xref ref-type="bibr" rid="pone.0010858-Stacey1">[28]</xref>, <xref ref-type="bibr" rid="pone.0010858-Rafnar1">[29]</xref>, <xref ref-type="bibr" rid="pone.0010858-Thorgeirsson1">[30]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson2">[31]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson3">[32]</xref>, <xref ref-type="bibr" rid="pone.0010858-Easton1">[33]</xref>. For 5 datasets, data were available only for the latter polymorphism either because the polymorphism was not available on the platform used or the SNP failed quality control criteria.</p><p>The contributing teams and datasets are shown in <xref ref-type="table" rid="pone-0010858-t001">Table 1</xref> with data on the number of cases and controls for each polymorphism and for each type of cancer. Datasets from the Framingham cohort contained imputed data for both polymorphisms since an Affymetrix platform had been used, rs4430796 data from the M.D. Anderson Cancer Center was imputed since this SNP had not been directly genotyped, and melanoma data from AMFS and Q-MEGA contained counts from pooling experiments, otherwise all other datasets had direct genotyping on individual participants. Detailed demographic and other characteristics of the study populations can be found in the respective primary publications of these GWA studies <xref ref-type="bibr" rid="pone.0010858-Tenesa1">[14]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gold1">[15]</xref>, <xref ref-type="bibr" rid="pone.0010858-Maris1">[16]</xref>, <xref ref-type="bibr" rid="pone.0010858-Cust1">[17]</xref>, <xref ref-type="bibr" rid="pone.0010858-Eeles1">[18]</xref>, <xref ref-type="bibr" rid="pone.0010858-Brennan1">[20]</xref>, <xref ref-type="bibr" rid="pone.0010858-Hung1">[21]</xref>, <xref ref-type="bibr" rid="pone.0010858-Amos1">[22]</xref>, <xref ref-type="bibr" rid="pone.0010858-Zanke1">[23]</xref>, <xref ref-type="bibr" rid="pone.0010858-Brown1">[24]</xref>, <xref ref-type="bibr" rid="pone.0010858-Yeager1">[25]</xref>, <xref ref-type="bibr" rid="pone.0010858-Duggan1">[26]</xref>, <xref ref-type="bibr" rid="pone.0010858-Tomlinson1">[27]</xref>, <xref ref-type="bibr" rid="pone.0010858-Stacey1">[28]</xref>, <xref ref-type="bibr" rid="pone.0010858-Rafnar1">[29]</xref>, <xref ref-type="bibr" rid="pone.0010858-Thorgeirsson1">[30]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson2">[31]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson3">[32]</xref>, <xref ref-type="bibr" rid="pone.0010858-httpwwwncbi1">[34]</xref>.</p><table-wrap id="pone-0010858-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0010858.t001</object-id><label>Table 1</label><caption><title>Characteristics of datasets included in the collaborative meta-analysis.</title></caption><alternatives><graphic id="pone-0010858-t001-1" xlink:href="pone.0010858.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Study Centre</td><td align="left" rowspan="1" colspan="1">Cancer</td><td align="left" rowspan="1" colspan="1">Genotyping platform(s)</td><td align="left" rowspan="1" colspan="1">rs4430796 #cases</td><td align="left" rowspan="1" colspan="1">rs4430796 #controls</td><td align="left" rowspan="1" colspan="1">rs7501939 #cases</td><td align="left" rowspan="1" colspan="1">rs7501939 #controls</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">*ARCTIC</td><td align="left" rowspan="1" colspan="1">colorectal<xref ref-type="bibr" rid="pone.0010858-Zanke1">[23]</xref></td><td align="left" rowspan="1" colspan="1">Sequenom homogenous MassExtend (in house)</td><td align="left" rowspan="1" colspan="1">1,079</td><td align="left" rowspan="1" colspan="1">1,089</td><td align="left" rowspan="1" colspan="1">1,075</td><td align="left" rowspan="1" colspan="1">1,087</td></tr><tr><td align="left" rowspan="1" colspan="1">*AMFS</td><td align="left" rowspan="1" colspan="1">melanoma<xref ref-type="bibr" rid="pone.0010858-Cust1">[17]</xref>, <xref ref-type="bibr" rid="pone.0010858-Brown1">[24]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K (pooled)</td><td align="left" rowspan="1" colspan="1">490 <italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">427 <italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">490 <italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">427 <italic><sup>p</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">Cambridge</td><td align="left" rowspan="1" colspan="1">breast <xref ref-type="bibr" rid="pone.0010858-Easton1">[33]</xref></td><td align="left" rowspan="1" colspan="1">Perlegen</td><td align="left" rowspan="1" colspan="1">387</td><td align="left" rowspan="1" colspan="1">363</td><td align="left" rowspan="1" colspan="1">387</td><td align="left" rowspan="1" colspan="1">363</td></tr><tr><td align="left" rowspan="1" colspan="1">*CGEMS</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-Thomas1">[11]</xref>, <xref ref-type="bibr" rid="pone.0010858-Yeager1">[25]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K</td><td align="left" rowspan="1" colspan="1">4,960</td><td align="left" rowspan="1" colspan="1">5,021</td><td align="left" rowspan="1" colspan="1">4,869</td><td align="left" rowspan="1" colspan="1">4,930</td></tr><tr><td align="left" rowspan="1" colspan="1">*CAPS</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-Duggan1">[26]</xref></td><td align="left" rowspan="1" colspan="1">Sequenom (in house)</td><td align="left" rowspan="1" colspan="1">2,874</td><td align="left" rowspan="1" colspan="1">1,708</td><td align="left" rowspan="1" colspan="1">2,865</td><td align="left" rowspan="1" colspan="1">1,707</td></tr><tr><td align="left" rowspan="1" colspan="1">*CORGI</td><td align="left" rowspan="1" colspan="1">colorectal<xref ref-type="bibr" rid="pone.0010858-Tomlinson1">[27]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1">908</td></tr><tr><td align="left" rowspan="1" colspan="1">deCODE</td><td align="left" rowspan="1" colspan="1">breast<xref ref-type="bibr" rid="pone.0010858-Stacey1">[28]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 300K</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">1,815</td><td align="left" rowspan="1" colspan="1">30,742</td></tr><tr><td align="left" rowspan="1" colspan="1">deCODE</td><td align="left" rowspan="1" colspan="1">colorectal<xref ref-type="bibr" rid="pone.0010858-Rafnar1">[29]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 300K</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">988</td><td align="left" rowspan="1" colspan="1">30,742</td></tr><tr><td align="left" rowspan="1" colspan="1">deCODE</td><td align="left" rowspan="1" colspan="1">lung<xref ref-type="bibr" rid="pone.0010858-Rafnar1">[29]</xref>, <xref ref-type="bibr" rid="pone.0010858-Thorgeirsson1">[30]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 300K</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">651</td><td align="left" rowspan="1" colspan="1">30,742</td></tr><tr><td align="left" rowspan="1" colspan="1">deCODE</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson2">[31]</xref>, <xref ref-type="bibr" rid="pone.0010858-Gudmundsson3">[32]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 300K</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">1619</td><td align="left" rowspan="1" colspan="1">30,742</td></tr><tr><td align="left" rowspan="1" colspan="1">*FHS</td><td align="left" rowspan="1" colspan="1">breast<xref ref-type="bibr" rid="pone.0010858-httpwwwncbi1">[34]</xref></td><td align="left" rowspan="1" colspan="1">Affymetrix 500K and MIPS 50K combined</td><td align="left" rowspan="1" colspan="1">182<italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">852 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">182 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">852 <italic><sup>i</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">*FHS</td><td align="left" rowspan="1" colspan="1">colorectal<xref ref-type="bibr" rid="pone.0010858-httpwwwncbi1">[34]</xref></td><td align="left" rowspan="1" colspan="1">Affymetrix 500K and MIPS 50K combined</td><td align="left" rowspan="1" colspan="1">108 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,498 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">108 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,498 <italic><sup>i</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">*FHS</td><td align="left" rowspan="1" colspan="1">lung<xref ref-type="bibr" rid="pone.0010858-httpwwwncbi1">[34]</xref></td><td align="left" rowspan="1" colspan="1">Affymetrix 500K and MIPS 50K combined</td><td align="left" rowspan="1" colspan="1">90 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,498 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">90 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,498 <italic><sup>i</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">*FHS</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-httpwwwncbi1">[34]</xref></td><td align="left" rowspan="1" colspan="1">Affymetrix 500K and MIPS 50K combined</td><td align="left" rowspan="1" colspan="1">190 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">646 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">190 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">646 <italic><sup>i</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">*IARC</td><td align="left" rowspan="1" colspan="1">lung<xref ref-type="bibr" rid="pone.0010858-Brennan1">[20]</xref>, <xref ref-type="bibr" rid="pone.0010858-Hung1">[21]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 300K</td><td align="left" rowspan="1" colspan="1">641</td><td align="left" rowspan="1" colspan="1">2,435</td><td align="left" rowspan="1" colspan="1">1,797</td><td align="left" rowspan="1" colspan="1">2,378</td></tr><tr><td align="left" rowspan="1" colspan="1">*JHH</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-Duggan1">[26]</xref></td><td align="left" rowspan="1" colspan="1">Sequenom (in house)</td><td align="left" rowspan="1" colspan="1">1,512</td><td align="left" rowspan="1" colspan="1">478</td><td align="left" rowspan="1" colspan="1">1,521</td><td align="left" rowspan="1" colspan="1">479</td></tr><tr><td align="left" rowspan="1" colspan="1">*MDACC</td><td align="left" rowspan="1" colspan="1">lung<xref ref-type="bibr" rid="pone.0010858-Amos1">[22]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 317K</td><td align="left" rowspan="1" colspan="1">1,152 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,137 <italic><sup>i</sup></italic></td><td align="left" rowspan="1" colspan="1">1,152</td><td align="left" rowspan="1" colspan="1">1,137</td></tr><tr><td align="left" rowspan="1" colspan="1">*PANSCAN</td><td align="left" rowspan="1" colspan="1">pancreatic Stage 1<xref ref-type="bibr" rid="pone.0010858-Petersen1">[19]</xref>, <xref ref-type="bibr" rid="pone.0010858-Petersen2">[48]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K and 610K</td><td align="left" rowspan="1" colspan="1">1,754</td><td align="left" rowspan="1" colspan="1">1,796</td><td align="left" rowspan="1" colspan="1">1,757</td><td align="left" rowspan="1" colspan="1">1,796</td></tr><tr><td align="left" rowspan="1" colspan="1">*PANSCAN</td><td align="left" rowspan="1" colspan="1">pancreatic Stage 2<xref ref-type="bibr" rid="pone.0010858-Petersen1">[19]</xref>, <xref ref-type="bibr" rid="pone.0010858-Petersen2">[48]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K and 610K</td><td align="left" rowspan="1" colspan="1">1,748</td><td align="left" rowspan="1" colspan="1">1,818</td><td align="left" rowspan="1" colspan="1">1,769</td><td align="left" rowspan="1" colspan="1">1,841</td></tr><tr><td align="left" rowspan="1" colspan="1">*Q-MEGA</td><td align="left" rowspan="1" colspan="1">melanoma<xref ref-type="bibr" rid="pone.0010858-Brown1">[24]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K (pooled)</td><td align="left" rowspan="1" colspan="1">864<italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">864 <italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">864 <italic><sup>p</sup></italic></td><td align="left" rowspan="1" colspan="1">864 <italic><sup>p</sup></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">*UKGPCS</td><td align="left" rowspan="1" colspan="1">prostate<xref ref-type="bibr" rid="pone.0010858-Eeles1">[18]</xref></td><td align="left" rowspan="1" colspan="1">Illumina 550K</td><td align="left" rowspan="1" colspan="1">1,609</td><td align="left" rowspan="1" colspan="1">1,797</td><td align="left" rowspan="1" colspan="1">1,834</td><td align="left" rowspan="1" colspan="1">1,867</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label></label><p>Unless otherwise indicated all data is from direct genotyping. *ARCTIC (Assessment of Risk for Colorectal Tumors in Canada), AMFS (Australian Melanoma Family Study), CGEMS (Cancer Genetics Markers of Susceptibility), CAPS (Cancer of the Prostate in Sweden), CORGI (Colorectal Tumour Gene Identification), FHS (Framingham Heart Study), IARC (International Agency for Research on Cancer), JHH (Johns Hopkins Hospital), MDACC (M.D. Anderson Cancer Center, Texas), PANSCAN (Pancreatic Cancer Cohort Consortium), Q-MEGA (Queensland study of Melanoma: Environment and Genetic Associations), UKGPCS (UK Genetic Prostate Cancer Study). n/a: no available data; <italic>i</italic>: imputed; <italic>p</italic>: pooled.</p></fn></table-wrap-foot></table-wrap><p>Overall, the collaborative analysis included data on rs4430796 for 19,640 cancer cases and 21,929 controls; for prostate cancer there were 11,145 cases and 9,650 controls, while for all other cancers there were 8,495 cases and 12,279 controls. The collected data on rs7501939 included 26,923 cases and 49,085 controls; for prostate cancer there were 12,898 cases and 40,371 controls, while for the other cancers there were 14,025 cases and 43,893 controls. Malignancies other than prostate cancer in these datasets included colorectal, breast, lung and pancreatic cancers, and melanoma (<xref ref-type="table" rid="pone-0010858-t001">Table 1</xref>). deCODE contributed data on 4 different cancers and had a common population control group for all 4 of them. The Framingham Heart Study (FHS) contributed data on 4 different cancers and had a common population control group (subjects ≥65 years at the last contact who are not nuclear family member of the cancer cases) for all 4 studies with the exception of prostate and breast cancer which used male and female only controls respectively. The common control groups for deCODE and FHS are only counted once in the total sample sizes above.</p><p>The meta-analysis of all datasets (<xref ref-type="table" rid="pone-0010858-t002">Table 2</xref>, <xref ref-type="fig" rid="pone-0010858-g001">Figure 1</xref>) showed a per T2D risk allele association with both rs4430796 (G allele OR 0.91 [95% CI: 0.88, 0.94] p = 3×10<sup>−10</sup>) and rs7501939 (T allele OR 0.91 [95% CI: 0.88, 0.94] p = 5v10<sup>−10</sup>) according to fixed effects calculations, while by random effects calculations there was nominal significance (OR 0.94 [95% CI: 0.88, 1.00], p = 0.033 for rs4430796 and 0.93 [95% CI: 0.86, 1.01], p = 0.07 for rs7501939). The reason for this diversity is that there was very large between-study heterogeneity in the effect sizes (I<sup>2</sup> of 82% [95% CI: 73-89%] and 80% [95% CI: 70-86%], respectively, for the two polymorphisms; Q-test p-value <0.001 for both polymorphisms), and this makes the fixed effects calculations less reliable. Results were qualitatively similar when we increased the variance in deCODE, FHS, and IARC estimates to account for the overlapping control group (not shown).</p><fig id="pone-0010858-g001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0010858.g001</object-id><label>Figure 1</label><caption><title>Association of rs4430796 and rs7501939 with diverse cancer types.</title><p>Panel A shows results for rs4430796 and panel B shows results for rs7501939. Each study is shown by its odds ratio and 95% confidence intervals). Prostate cancer studies appear on the top and other cancer studies follow in alphabetical order. For the abbreviations of the names of the studies see <xref ref-type="table" rid="pone-0010858-t001">Table 1</xref>. The summary diamond at the bottom corresponds to the fixed effects summary. Weight indicates the relative proportion of the total evidence found in each study (the weight is inversely proportional to the variance).</p></caption><graphic xlink:href="pone.0010858.g001"></graphic></fig><table-wrap id="pone-0010858-t002" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0010858.t002</object-id><label>Table 2</label><caption><title>Summary of results for association between rs4430796 and rs7501939 and diverse cancer types.</title></caption><alternatives><graphic id="pone-0010858-t002-2" xlink:href="pone.0010858.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">rs4430796</td><td align="left" rowspan="1" colspan="1">rs4430796</td><td align="left" rowspan="1" colspan="1">rs4430796</td><td align="left" rowspan="1" colspan="1">rs7501939</td><td align="left" rowspan="1" colspan="1">rs7501939</td><td align="left" rowspan="1" colspan="1">rs7501939</td></tr><tr><td align="left" rowspan="1" colspan="1">Cancer type</td><td align="left" rowspan="1" colspan="1">Studies (cases, controls)</td><td align="left" rowspan="1" colspan="1">OR (95% CI)</td><td align="left" rowspan="1" colspan="1">I<sup>2</sup> (95% CI)</td><td align="left" rowspan="1" colspan="1">Studies (cases, controls)</td><td align="left" rowspan="1" colspan="1">OR (95% CI)</td><td align="left" rowspan="1" colspan="1">I<sup>2</sup> (95% CI)</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">All cancers</td><td align="left" rowspan="1" colspan="1">16 (19,640, 21,929)*</td><td align="left" rowspan="1" colspan="1">0.91 (0.88, 0.94)</td><td align="left" rowspan="1" colspan="1">82 (73, 89)</td><td align="left" rowspan="1" colspan="1">21 (26,923, 49,085)*</td><td align="left" rowspan="1" colspan="1">0.92 (0.90, 0.95)</td><td align="left" rowspan="1" colspan="1">80 (70, 86)</td></tr><tr><td align="left" rowspan="1" colspan="1">Prostate</td><td align="left" rowspan="1" colspan="1">5 (11,145, 9,650)</td><td align="left" rowspan="1" colspan="1">0.79 (0.76, 0.83)</td><td align="left" rowspan="1" colspan="1">42 (0, 79)</td><td align="left" rowspan="1" colspan="1">6 (12,898, 40,371)</td><td align="left" rowspan="1" colspan="1">0.80 (0.77, 0.83)</td><td align="left" rowspan="1" colspan="1">56 (0, 82)</td></tr><tr><td align="left" rowspan="1" colspan="1">All Others</td><td align="left" rowspan="1" colspan="1">11 (8,495, 12,279)*</td><td align="left" rowspan="1" colspan="1">1.03 (0.99, 1.07)</td><td align="left" rowspan="1" colspan="1">0 (0, 60)</td><td align="left" rowspan="1" colspan="1">15 (14,025, 43,893)*</td><td align="left" rowspan="1" colspan="1">1.00 (0.97, 1.04)</td><td align="left" rowspan="1" colspan="1">0 (0, 54)</td></tr><tr><td align="left" rowspan="1" colspan="1">Breast</td><td align="left" rowspan="1" colspan="1">2 (569, 1,215)</td><td align="left" rowspan="1" colspan="1">1.00 (0.84, 1.20)</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">3 (2,384, 31,957)</td><td align="left" rowspan="1" colspan="1">0.97 (0.91, 1.04)</td><td align="left" rowspan="1" colspan="1">0 (0, 90)</td></tr><tr><td align="left" rowspan="1" colspan="1">Lung</td><td align="left" rowspan="1" colspan="1">3 (1,883, 5,070)</td><td align="left" rowspan="1" colspan="1">1.05 (0.98, 1.13)</td><td align="left" rowspan="1" colspan="1">0 (0, 90)</td><td align="left" rowspan="1" colspan="1">4 (3,690, 35,755)</td><td align="left" rowspan="1" colspan="1">1.03 (0.96, 1.10)</td><td align="left" rowspan="1" colspan="1">0 (0, 85)</td></tr><tr><td align="left" rowspan="1" colspan="1">Colorectal</td><td align="left" rowspan="1" colspan="1">2 (1,187, 2,587)</td><td align="left" rowspan="1" colspan="1">1.01 (0.90, 1.14)</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">4 (3,071, 34,235)</td><td align="left" rowspan="1" colspan="1">1.01 (0.94, 1.08)</td><td align="left" rowspan="1" colspan="1">0 (0, 85)</td></tr><tr><td align="left" rowspan="1" colspan="1">Melanoma</td><td align="left" rowspan="1" colspan="1">2 (1,354, 1,291)</td><td align="left" rowspan="1" colspan="1">0.98 (0.87, 1.01)</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">2 (1,354, 1,291)</td><td align="left" rowspan="1" colspan="1">1.01 (0.90, 1.13)</td><td align="left" rowspan="1" colspan="1">n/a</td></tr><tr><td align="left" rowspan="1" colspan="1">Pancreatic</td><td align="left" rowspan="1" colspan="1">2 (3,502, 3,614)</td><td align="left" rowspan="1" colspan="1">1.04 (0.98, 1.11)</td><td align="left" rowspan="1" colspan="1">n/a</td><td align="left" rowspan="1" colspan="1">2 (3,526, 3,637)</td><td align="left" rowspan="1" colspan="1">1.03 (0.97, 1.10)</td><td align="left" rowspan="1" colspan="1">n/a</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt102"><label></label><p>OR: odds ratio, CI: confidence interval, n/a: not applicable (heterogeneity I<sup>2</sup> confidence intervals are not calculated when there are only 2 studies). Odds ratios are based on fixed effects calculations. When point estimates or confidence intervals differ by over 1% in random effects calculations, random effects results are mentioned in the text. * the common control groups of deCODE and FHS are counted only once.</p></fn></table-wrap-foot></table-wrap><p>The heterogeneity was largely driven by the diversity in the effect sizes between prostate cancer and all other cancers. A meta-analysis limited to prostate cancer datasets gave consistent associations with both rs4430796 (OR per copy of T2D risk allele (A) 0.79 [95% CI: 0.76, 0.83], p<10<sup>−15</sup> by fixed effects and 0.79 [95% CI: 0.74, 0.84] p = 10<sup>−13</sup> by random effects), and rs7501939 (OR per copy of T2D risk allele (T) 0.80 [95% CI: 0.77, 0.83] p<10<sup>−15</sup> by fixed effects and 0.79 [95% CI: 0.74, 0.85], p = 2×10<sup>−11</sup> by random effects) (<xref ref-type="table" rid="pone-0010858-t002">Table 2</xref>). There was some residual between-study heterogeneity even within the prostate cancer datasets (I<sup>2</sup> of 42% [95%CI: 0–79%] and 56% [95% CI: 0–82%], respectively, for the two polymorphisms; Q-test p-value 0.037 and 0.14, respectively), although the heterogeneity pertained only to the exact magnitude of the genetic effects and a nominally statistically significant association was seen in each of the datasets except for the Framingham study where the number of prostate cancer cases was more limited.</p><p>Conversely, the results for all other cancers suggested no significant association and results were consistent across studies. The summary OR was 1.03 and 1.00 for the two polymorphisms respectively (p = 0.14 and 0.81 by fixed effects) and the 95% CIs excluded ORs deviating more than 7% from the null (OR = 1.00) for rs4430796 and more than 4% from the null for rs7501939 (<xref ref-type="table" rid="pone-0010858-t002">Table 2</xref>). The Q-test p-value was 0.99 and 0.45 for the two polymorphisms respectively and random effects estimates were thus identical to fixed effects estimates.</p><p>There was also no convincing evidence for an association between either of the two polymorphisms and any of the other cancers (besides prostate cancer), when each cancer type was evaluated separately. Point estimates were in the opposite direction (odds ratio 1.03–1.05) for pancreatic and lung cancer, but were not nominally statistically significant (<xref ref-type="table" rid="pone-0010858-t002">Table 2</xref>). The difference between the prostate cancer and other cancers' effect estimates was beyond chance (p<0.05) for both polymorphisms.</p></sec></sec><sec id="s3"><title>Discussion</title><p>The current collaborative analysis documents that both rs4430796 and rs7501939 have robust support for association with prostate cancer, while we did not observe any convincing evidence for an association of any of the other cancers examined with either polymorphism. When data from all other cancers, excluding prostate cancer, were combined the summary effects had 95% CIs that excluded even subtle associations. Apart from prostate cancer, when other datasets for each individual cancer type was combined, the 95% CIs consistently excluded associations with modest effects. This would suggest that the effects mediated by these polymorphisms are specific to T2D and prostate cancer and they do not involve any other cancer types.</p><p>The <italic>HNF1B</italic> gene encodes a transcription factor and it was initially identified as a MODY gene<xref ref-type="bibr" rid="pone.0010858-Horikawa1">[13]</xref>. Subsequent studies have suggested that mutations in this gene may also be related to renal disease<xref ref-type="bibr" rid="pone.0010858-Edghill1">[35]</xref> and chromophobe renal cell carcinoma<xref ref-type="bibr" rid="pone.0010858-Rebouissou1">[36]</xref>. No GWAS evaluating kidney cancer were included in our analysis, and no kidney cancer GWAS has been published to-date. The expression profile of the gene shows a tissue-specific pattern. It is essential for embryonic survival and is expressed in the gut, kidney, liver, lung, pancreas, prostate, thymus and genital tract <xref ref-type="bibr" rid="pone.0010858-Reber1">[37]</xref>, <xref ref-type="bibr" rid="pone.0010858-Coffinier1">[38]</xref>. It could be speculated that the lack of association with some cancers studied here may be due to the low or absent expression of this gene in those tissues (for example breast cancer). We did not have data on liver cancer, thymoma or genital tract cancer, but data on lung, pancreatic, and colorectal cancer showed no association, with point estimates very near to the null.</p><p>The two variants that we assessed are not necessarily the functional culprits. GWA studies typically derive markers of phenotypes that are probably linked with the functional genetic variation<xref ref-type="bibr" rid="pone.0010858-Ioannidis1">[39]</xref>. However, identifying the functional variants is difficult. Even if they could be identified, it is unlikely that substantially large genetic effects for other cancers would exist, if the tagging variants have so consistently null effects. Another caveat is that we only examined populations of Caucasian descent. This reduces the heterogeneity that could be due to different LD patterns in populations of different ancestry. However, it would be worthwhile to investigate the associations of the <italic>HNF1B</italic> variants for T2D, prostate cancer, and other cancers, also in non-Caucasian populations. Preliminary data suggest that both of the examined variants had consistent associations with T2D in Caucasian, Asian (Hong Kong), and West African ancestry participants<xref ref-type="bibr" rid="pone.0010858-Gudmundsson1">[9]</xref>, while the association of rs4430796 with prostate cancer risk was found to be even stronger in the Japanese than in Caucasian populations<xref ref-type="bibr" rid="pone.0010858-Yamada1">[40]</xref>. Moreover, it would be useful to dissect associations with specific disease subsets. Even within the analyzed Caucasian-descent populations, we observed some modest between-study heterogeneity in the strength of the association between the <italic>HNF1B</italic> variants and prostate cancer. This may be due to different associations in different sub-phenotypes. For example, some data suggest that the rs4430796 A allele may primarily increase the risk for early-onset (<50 years) prostate cancer rather than later-onset disease<xref ref-type="bibr" rid="pone.0010858-Levin1">[41]</xref>.</p><p>In conclusion, while the two examined <italic>HNF1B</italic> variants conclusively have pleiotropic effects on both T2D and prostate cancer, the pleiotropy apparently does not extend to other cancer types. Genetic effects may offer a way to dissect comorbidity between specific cancers and metabolic phenotypes. Besides <italic>HNF1B</italic>, other gene loci have started appearing where variants are identified that modulate susceptibility to both T2D and some malignancy, e.g. prostate cancer for the <italic>JAZF1</italic> locus gene <xref ref-type="bibr" rid="pone.0010858-Thomas1">[11]</xref>, <xref ref-type="bibr" rid="pone.0010858-Zeggini1">[42]</xref> and melanoma for the <italic>CDKN2A</italic> locus <xref ref-type="bibr" rid="pone.0010858-Zeggini2">[43]</xref>, although different, unlinked variants are implicated in the susceptibility to the malignancy and T2D, respectively. The elucidation of correlated pleiotropic effects on diverse phenotypes will require very large studies, given the generally subtle effects involved. Collaborative efforts between multiple teams, as in the current study, may offer a suitable approach to answer such questions.</p></sec><sec id="s4" sec-type="methods"><title>Methods</title><sec id="s4a"><title>Eligible GWA investigations and data</title><p>We used the NHGRI catalogue of published GWA studies<xref ref-type="bibr" rid="pone.0010858-Hindorff1">[44]</xref>, a comprehensive database of GWA investigations to identify GWA studies on cancer phenotypes published as of May 20, 2008. We also performed additional PubMed searches to identify whether any additional GWA studies on cancer phenotypes had been published until then. We focused on solid cancers, excluding hematologic malignancies. Given that these GWAS did not include any studies on pancreatic cancer (of special interest, given the association with T2D), we also identified GWAS on pancreatic cancer that had not been published by that time, so as to ensure their inclusion.</p><p>We communicated with the corresponding and principal investigators of all of these studies to request their participation in the collaborative meta-analysis. The investigators of these studies were asked to contribute relevant data on genotype frequencies in cancer cases and non-cancer controls for the <italic>HNF1B</italic> variants, rs4430796 and rs7501939. The risk alleles for prostate cancer are A and C for rs4430796 and rs7501939 respectively. The risk alleles for T2D are G and T for rs4430796 and rs7501939 respectively. The two SNPs have modestly high LD in Caucasians, but low LD in Africans (r<sup>2</sup> = 0.77 and 0.22 in CEU and YRI, respectively). Investigators were requested to provide all GWA data that they had obtained for evaluation of any cancer phenotype, including any additional unpublished datasets. Additional genotyping for the two specific variants was encouraged, when a GWA platform had been used that did not directly genotype these polymorphisms (e.g. Affymetrix or Perlegen rather than Illumina). When a study had data on more than one cancer type, data were requested to be provided separately for each cancer type. Investigators were asked to provide also information and clarifications about the design of their studies, and to ensure that population stratification and cryptic relatedness had been appropriately addressed and appropriate quality controls were available for the genotyping. All GWAS investigations that contributed data on these SNPs used stringent QC standards (as described in detail in their original publications) and the two SNPs fulfilled these standards. Approval from local institutional review boards and steering committees was obtained, as deemed necessary for each study by its investigators. The contributed data were checked for completeness and with logical queries and any missing or unclear information was clarified through communication with the contributing investigators.</p></sec><sec id="s4b"><title>Meta-analysis</title><p>For each SNP, we performed meta-analyses including the data from all eligible cancer studies (regardless of the specific cancer phenotype addressed) and also subgroup meta-analyses, with each subgroup limited to studies addressing a specific cancer phenotype. A separate analysis compared the results of the association for prostate cancer versus the association for all other cancers combined.</p><p>All analyses followed the per allele (log-additive) model of inheritance with effect sizes expressed in the odds ratio (OR) scale using both fixed and random effects models<xref ref-type="bibr" rid="pone.0010858-Kavvoura1">[45]</xref>. Heterogeneity testing used the Q statistic (considered statistically significant at p<0.10), and the I<sup>2</sup> metric<xref ref-type="bibr" rid="pone.0010858-Higgins1">[46]</xref> and its 95% CIs <xref ref-type="bibr" rid="pone.0010858-Ioannidis2">[47]</xref>. Analyses excluding data from studies with pooled genotyping gave similar results (not shown).</p><p>Based on the accumulated total sample size and given the minor allele frequencies of these two polymorphisms in HapMap CEU (47% for rs4430796 A allele and 47% for rs7501939 T allele), the meta-analysis had 95% or higher power to detect an association of OR = 1.10 at alpha = 0.05 with each of the two polymorphisms for overall cancer risk, prostate cancer risk, or other cancer risk. Reported p-values are two-tailed. Analyses were performed in STATA 10.0 (College Station, Texas).</p></sec></sec></body><back><ack><p><bold>Australian Melanoma Family Study investigators</bold>: Graham J Mann<sup>1</sup>, John L Hopper<sup>2</sup>, Joanne F Aitken<sup>3</sup>, Richard F Kefford<sup>1</sup>, Graham G Giles<sup>4</sup>, Bruce K Armstrong<sup>5</sup>.</p><p><sup>1</sup>Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead, New South Wales, Australia. <sup>2</sup>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria, Australia. <sup>3</sup>Viertel Centre for Research in Cancer Control, The Cancer Council Queensland, Brisbane, Queensland, Australia. <sup>4</sup>Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia. <sup>5</sup>School of Public Health, University of Sydney, New South Wales, Australia.</p><p><bold>PanScan Consortium</bold>: Gloria M. Petersen*<sup>1</sup>, Laufey Amundadottir*<sup>2,3</sup>, Charles S. Fuchs*<sup>4,5</sup>, Peter Kraft*<sup>6,7</sup>, Rachael Z. Stolzenberg-Solomon*<sup>3</sup>, Kevin B. Jacobs <sup>3,8,9</sup>, Alan A. Arslan<sup>10,11,12</sup>, H. Bas Bueno-de-Mesquita<sup>13</sup>, Steven Gallinger<sup>14</sup>, Myron Gross<sup>15</sup>, Kathy Helzlsouer<sup>16</sup>, Elizabeth A. Holly<sup>17</sup>, Eric J. Jacobs<sup>18</sup>, Alison P. Klein<sup>19,20</sup>, Andrea LaCroix<sup>21</sup>, Donghui Li<sup>22</sup>, Margaret T. Mandelson<sup>21,23</sup>, Sara H. Olson<sup>24</sup>, Harvey A. Risch<sup>25</sup>, Wei Zheng<sup>26</sup>, Demetrius Albanes<sup>3</sup>, William R. Bamlet<sup>1</sup>, Christine D. Berg <sup>27</sup>, Marie-Christine Boutron-Ruault<sup>28</sup>, Julie E. Buring<sup>29,30</sup>, Paige M. Bracci<sup>17</sup>, Federico Canzian<sup>31</sup>, Sandra Clipp<sup>32</sup>, Michelle Cotterchio<sup>33</sup>, Mariza de Andrade<sup>1</sup>, Eric J. Duell<sup>34</sup>, J. Michael Gaziano<sup>35,36</sup>, Edward L. Giovannucci<sup>5,6,37</sup>, Michael Goggins<sup>38</sup>, Göran Hallmans<sup>39</sup>, Susan E. Hankinson<sup>5,6</sup>, Manal Hassan<sup>22</sup>, Barbara Howard<sup>40</sup>, David J. Hunter<sup>5,6</sup>, Amy Hutchinson<sup>3,8</sup>, Mazda Jenab<sup>34</sup>, Rudolf Kaaks<sup>31</sup>, Charles Kooperberg<sup>21</sup>, Vittorio Krogh<sup>41</sup>, Robert C. Kurtz<sup>42</sup>, Shannon M. Lynch<sup>3</sup>, Robert R. McWilliams<sup>1</sup>, Julie B. Mendelsohn<sup>3</sup>, Dominique S. Michaud<sup>6,43</sup>, Hemang Parikh<sup>2,3</sup>, Alpa V. Patel<sup>18</sup>, Petra H.M. Peeters<sup>43,44</sup>, Aleksandar Rajkovic<sup>45</sup>, Elio Riboli<sup>43</sup>, Laudina Rodriguez<sup>46</sup>, Daniela Seminara<sup>47</sup>, Xiao-Ou Shu<sup>26</sup>, Gilles Thomas<sup>3,48</sup>, Anne Tjønneland<sup>49</sup>, Geoffrey S. Tobias<sup>3</sup>, Dimitrios Trichopoulos<sup>6,50</sup>, Stephen K. Van Den Eeden<sup>51</sup>, Jarmo Virtamo<sup>52</sup>, Jean Wactawski-Wende<sup>53</sup>, Zhaoming Wang<sup>3,8</sup>, Brian M. Wolpin<sup>4,5</sup>, Herbert Yu<sup>25</sup>, Kai Yu<sup>3</sup>, Anne Zeleniuch-Jacquotte<sup>11,12</sup>, Joseph F. Fraumeni, Jr.<sup>3</sup>, Robert N. Hoover*<sup>3</sup>, Patricia Hartge*<sup>3</sup>, Stephen J. Chanock*<sup>2,3</sup>.</p><p><sup>1</sup>Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, USA. <sup>2</sup>Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. <sup>3</sup>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MD, USA. <sup>4</sup>Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. <sup>5</sup>Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. <sup>6</sup>Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. <sup>7</sup>Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. <sup>8</sup>Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA. <sup>9</sup>Bioinformed Consulting Services, Gaithersburg, MD, USA. <sup>10</sup>Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA. <sup>11</sup>Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA. <sup>12</sup>New York University Cancer Institute, New York, NY, USA. <sup>13</sup>National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands and Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands. <sup>14</sup>Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. <sup>15</sup>Department of Laboratory Medicine/Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA. <sup>16</sup>Prevention and Research Center, Mercy Medical Center, Baltimore, MD, USA. <sup>17</sup>Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. <sup>18</sup>Department of Epidemiology, American Cancer Society, Atlanta, GA, USA. <sup>19</sup>Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. <sup>20</sup>Department of Epidemiology, the Bloomberg School of Public Health, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. <sup>21</sup>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. <sup>22</sup>Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. <sup>23</sup>Group Health Center for Health Studies, Seattle, WA, USA. <sup>24</sup>Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. <sup>25</sup>Yale University School of Public Health, New Haven, CT, USA. <sup>26</sup>Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. <sup>27</sup>Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. <sup>28</sup>Inserm, Paris-Sud University, Institut Gustave-Roussy, Villejuif, France. <sup>29</sup>Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. <sup>30</sup>Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA, USA. <sup>31</sup>German Cancer Research Center (DKFZ), Heidelberg, Germany. <sup>32</sup>Johns Hopkins Bloomberg School of Public Health, George W. Comstock Center for Public Health Research and Prevention, Hagerstown, MD, USA. <sup>33</sup>Cancer Care Ontario and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. <sup>34</sup>Catalan Institute of Oncology (ICO), Barcelona, Spain. <sup>35</sup>Physicians' Health Study, Divisions of Aging, Cardiovascular Disease, and Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. <sup>36</sup>Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA, USA. <sup>37</sup>Department of Nutrition, Harvard School of Public Health, Boston, MA, USA. <sup>38</sup>Departments of Oncology, Pathology and Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. <sup>39</sup>Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden. <sup>40</sup>MedStar Research Institute, Georgetown University, Hyattsville, MD <sup>41</sup>Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumoridi Milano, Milan, Italy. <sup>42</sup>Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. <sup>43</sup>Divisionof Epidemiology, Public Health and Primary Care, Imperial College London, London, UK. <sup>44</sup>Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. <sup>45</sup>Departments of Obstetrics and Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA <sup>46</sup>Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain. <sup>47</sup>Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA. <sup>48</sup>Synergie-Lyon-Cancer, INSERM U590, Centre Leon Berard, 69373 Lyon, Cedex <sup>08</sup>, France <sup>49</sup>Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. <sup>50</sup>Bureau of Epidemiologic Research, Academy of Athens, Greece <sup>51</sup>Division of Research, Kaiser Permanente, Northern California Region, Oakland, CA, USA. <sup>52</sup>Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. <sup>53</sup>Department of Social and Preventive Medicine, University at Buffalo, SUNY Buffalo, NY, USA.</p></ack><fn-group><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="financial-disclosure"><p><bold>Funding: </bold>JPAI is supported by funding for the Tufts Clinical and Translational Science Institute and the Center for Genetic Epidemiology and Modeling is supported by grant UL1 RR025752 from the National Institutes of Health. KSE is supported by the Wellcome Trust (WT075491/Z/04). EZ is supported by the Wellcome Trust (WT088885/Z/09/Z). NH and SM were funded by the Australian National Health and Medical Research Council (NHMRC) and the National Institutes of Health (grant R01-CA88363). HG is supported by Swedish Cancer Society (Cancerfonden), Swedish Research Council, and Linneus grant “Predication and prevention of breast cancer and prostate cancer”. RE and KM are supported by Cancer Research UK Grant C5047/A8385; C5047/A7357, The Institute of Cancer Research and The Everyman Campaign and The Prostate Cancer Research Foundation. The authors acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. DEN, JLD and FCH would like to acknowledge the support of the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK. The Prostate Testing for Cancer and Treatment (ProtecT) study is funded by the UK National Institute for Health Research Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The NCRI provided funding through ProMPT (Prostate Mechanisms of Progression and Treatment) and this support is gratefully acknowledged. The Cambridge prostate biorepository also received funding from the NIHR Comprehensive Biomedical Research Centre Grant. This support is gratefully acknowledged. The views and opinions expressed therein are those of the authors and are not necessarily those of the funding bodies. deCODE acknowledges grant support from the 6th Framework Program of the EU: contract 018827 (Polygene). The Australian Melanoma Family Study (AMFS) was supported by grants from the NHMRC, Cancer Councils of Queensland, NSW and Victoria, and by National Institutes of Health grant RO1-CA83115 to the GenoMEL consortium. The Framingham Heart Study (FHS) The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. 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