FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer
Identifieur interne : 006B03 ( Main/Exploration ); précédent : 006B02; suivant : 006B04FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer
Auteurs : Daniel J. Park [Australie] ; Fabrice A. Odefrey [Australie] ; Fleur Hammet [Australie] ; Graham G. Giles [Australie] ; Laura Baglietto [Australie] ; ABCFS [Australie] ; MCCS [Australie] ; John L. Hopper [Australie] ; Daniel F. Schmidt [Australie] ; Enes Makalic [Australie] ; Olga M. Sinilnikova [France] ; David E. Goldgar [États-Unis] ; Melissa C. Southey [Australie]Source :
- Breast cancer research and treatment [ 0167-6806 ] ; 2011.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39-1.61], P = 0.50 and OR = 0.74, 95% CI[0.41-1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.
Affiliations:
- Australie, France, États-Unis
- Auvergne-Rhône-Alpes, Rhône-Alpes, Victoria (État)
- Lyon, Melbourne
- Université de Melbourne
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Park</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Cancer Epidemiology Centre, The Cancer Council Victoria</s1><s2>Melbourne, VIC</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Melbourne, VIC</wicri:noRegion></affiliation></author><author><name sortKey="Odefrey, Fabrice A" sort="Odefrey, Fabrice A" uniqKey="Odefrey F" first="Fabrice A." last="Odefrey">Fabrice A. Odefrey</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Hammet, Fleur" sort="Hammet, Fleur" uniqKey="Hammet F" first="Fleur" last="Hammet">Fleur Hammet</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Abcfs" sort="Abcfs" uniqKey="Abcfs" last="Abcfs">ABCFS</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Australian Breast Cancer Family Study</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>6 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Mccs" sort="Mccs" uniqKey="Mccs" last="Mccs">MCCS</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Melbourne Collaborative Cohort Study</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F." last="Schmidt">Daniel F. Schmidt</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M." last="Sinilnikova">Olga M. Sinilnikova</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>INSERM U1052, CNRS UMR5286, Universite Lyon 1, Centre de Recherche En Cancérologie de Lyon, and Unite Mixte de Genetique Constitutionelle Des Cancers Frequents, Centre Hospitalier Universitaire de Lyon/Centre Leon Berard</s1><s2>Lyon</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Department of Dermatology, University of Utah School of Medicine</s1><s2>Salt Lake City, UT</s2><s3>USA</s3><sZ>12 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Salt Lake City, UT</wicri:noRegion></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0019480</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 12-0019480 INIST</idno><idno type="RBID">Pascal:12-0019480</idno><idno type="wicri:Area/PascalFrancis/Corpus">001726</idno><idno type="wicri:Area/PascalFrancis/Curation">004783</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">001A97</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">001A97</idno><idno type="wicri:doubleKey">0167-6806:2011:Park D:fan:variants:identified</idno><idno type="wicri:Area/Main/Merge">006F48</idno><idno type="wicri:Area/Main/Curation">006B03</idno><idno type="wicri:Area/Main/Exploration">006B03</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer</title><author><name sortKey="Park, Daniel J" sort="Park, Daniel J" uniqKey="Park D" first="Daniel J." last="Park">Daniel J. Park</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Cancer Epidemiology Centre, The Cancer Council Victoria</s1><s2>Melbourne, VIC</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Melbourne, VIC</wicri:noRegion></affiliation></author><author><name sortKey="Odefrey, Fabrice A" sort="Odefrey, Fabrice A" uniqKey="Odefrey F" first="Fabrice A." last="Odefrey">Fabrice A. Odefrey</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Hammet, Fleur" sort="Hammet, Fleur" uniqKey="Hammet F" first="Fleur" last="Hammet">Fleur Hammet</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Abcfs" sort="Abcfs" uniqKey="Abcfs" last="Abcfs">ABCFS</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Australian Breast Cancer Family Study</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>6 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Mccs" sort="Mccs" uniqKey="Mccs" last="Mccs">MCCS</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Melbourne Collaborative Cohort Study</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F." last="Schmidt">Daniel F. Schmidt</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, 207 Bouverie Street</s1><s2>Carlton, VIC 3053</s2><s3>AUS</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Carlton, VIC 3053</wicri:noRegion><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M." last="Sinilnikova">Olga M. Sinilnikova</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>INSERM U1052, CNRS UMR5286, Universite Lyon 1, Centre de Recherche En Cancérologie de Lyon, and Unite Mixte de Genetique Constitutionelle Des Cancers Frequents, Centre Hospitalier Universitaire de Lyon/Centre Leon Berard</s1><s2>Lyon</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Department of Dermatology, University of Utah School of Medicine</s1><s2>Salt Lake City, UT</s2><s3>USA</s3><sZ>12 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Salt Lake City, UT</wicri:noRegion></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne</s1><s2>Melbourne, VIC 3010</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author></analytic><series><title level="j" type="main">Breast cancer research and treatment</title><title level="j" type="abbreviated">Breast cancer res. treat.</title><idno type="ISSN">0167-6806</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Breast cancer research and treatment</title><title level="j" type="abbreviated">Breast cancer res. treat.</title><idno type="ISSN">0167-6806</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Age of onset</term><term>Breast cancer</term><term>Early</term><term>Exome sequencing</term><term>Genetic variability</term><term>Genotype</term><term>Risk factor</term><term>Variant</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Variant</term><term>Variabilité génétique</term><term>Génotype</term><term>Précoce</term><term>Age apparition</term><term>Cancer du sein</term><term>Facteur risque</term><term>Séquençage de l'exome</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39-1.61], P = 0.50 and OR = 0.74, 95% CI[0.41-1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>États-Unis</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Rhône-Alpes</li><li>Victoria (État)</li></region><settlement><li>Lyon</li><li>Melbourne</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><country name="Australie"><region name="Victoria (État)"><name sortKey="Park, Daniel J" sort="Park, Daniel J" uniqKey="Park D" first="Daniel J." last="Park">Daniel J. Park</name></region><name sortKey="Abcfs" sort="Abcfs" uniqKey="Abcfs" last="Abcfs">ABCFS</name><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><name sortKey="Hammet, Fleur" sort="Hammet, Fleur" uniqKey="Hammet F" first="Fleur" last="Hammet">Fleur Hammet</name><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><name sortKey="Mccs" sort="Mccs" uniqKey="Mccs" last="Mccs">MCCS</name><name sortKey="Odefrey, Fabrice A" sort="Odefrey, Fabrice A" uniqKey="Odefrey F" first="Fabrice A." last="Odefrey">Fabrice A. Odefrey</name><name sortKey="Park, Daniel J" sort="Park, Daniel J" uniqKey="Park D" first="Daniel J." last="Park">Daniel J. Park</name><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F." last="Schmidt">Daniel F. Schmidt</name><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M." last="Sinilnikova">Olga M. Sinilnikova</name></region></country><country name="États-Unis"><noRegion><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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