LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma
Identifieur interne : 007064 ( Main/Merge ); précédent : 007063; suivant : 007065LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma
Auteurs : Jacky T. Yeung [États-Unis] ; Ronald L. Hamilton [États-Unis] ; Koji Ohnishi [États-Unis] ; Maki Ikeura [États-Unis] ; Douglas M. Potter [États-Unis] ; Marina N. Nikiforova [États-Unis] ; Soldano Ferrone [États-Unis] ; Regina I. Jakacki [États-Unis] ; Ian F. Pollack [États-Unis] ; Hideho Okada [États-Unis]Source :
- Clinical cancer research [ 1078-0432 ] ; 2013.
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Abstract
Purpose: Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or β-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. Experimental Design: In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed, paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8+ T-cell infiltration. Results: LOH in HLA class I, B2m, HLA class II, HLA class III, and 6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA class I expression correlated with intratumoral CD8+ T-cell infiltration. Conclusion: LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests a crucial role for these genes in immunosurveillance.
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Yeung</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Pathology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Ohnishi, Koji" sort="Ohnishi, Koji" uniqKey="Ohnishi K" first="Koji" last="Ohnishi">Koji Ohnishi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Ikeura, Maki" sort="Ikeura, Maki" uniqKey="Ikeura M" first="Maki" last="Ikeura">Maki Ikeura</name><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Potter, Douglas M" sort="Potter, Douglas M" uniqKey="Potter D" first="Douglas M." last="Potter">Douglas M. Potter</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="07"><s1>Biostatistics Facility, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Nikiforova, Marina N" sort="Nikiforova, Marina N" uniqKey="Nikiforova M" first="Marina N." last="Nikiforova">Marina N. Nikiforova</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Pathology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Ferrone, Soldano" sort="Ferrone, Soldano" uniqKey="Ferrone S" first="Soldano" last="Ferrone">Soldano Ferrone</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Jakacki, Regina I" sort="Jakacki, Regina I" uniqKey="Jakacki R" first="Regina I." last="Jakacki">Regina I. 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Yeung</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Pathology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Ohnishi, Koji" sort="Ohnishi, Koji" uniqKey="Ohnishi K" first="Koji" last="Ohnishi">Koji Ohnishi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Ikeura, Maki" sort="Ikeura, Maki" uniqKey="Ikeura M" first="Maki" last="Ikeura">Maki Ikeura</name><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Potter, Douglas M" sort="Potter, Douglas M" uniqKey="Potter D" first="Douglas M." last="Potter">Douglas M. Potter</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="07"><s1>Biostatistics Facility, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Nikiforova, Marina N" sort="Nikiforova, Marina N" uniqKey="Nikiforova M" first="Marina N." last="Nikiforova">Marina N. Nikiforova</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Pathology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Ferrone, Soldano" sort="Ferrone, Soldano" uniqKey="Ferrone S" first="Soldano" last="Ferrone">Soldano Ferrone</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Jakacki, Regina I" sort="Jakacki, Regina I" uniqKey="Jakacki R" first="Regina I." last="Jakacki">Regina I. Jakacki</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Pediatrics, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Pediatrics, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation></author><author><name sortKey="Pollack, Ian F" sort="Pollack, Ian F" uniqKey="Pollack I" first="Ian F." last="Pollack">Ian F. Pollack</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Okada, Hideho" sort="Okada, Hideho" uniqKey="Okada H" first="Hideho" last="Okada">Hideho Okada</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurological Surgery, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Neurological Surgery, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</s1><s3>USA</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Department of Surgery and Immunology, University of Pittsburgh School of Medicine</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Brain Tumor Program, University of Pittsburgh Cancer Institute, University of Pittsburgh</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Clinical cancer research</title><title level="j" type="abbreviated">Clin. cancer res.</title><idno type="ISSN">1078-0432</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Clinical cancer research</title><title level="j" type="abbreviated">Clin. cancer res.</title><idno type="ISSN">1078-0432</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Chromosome C6</term><term>Class I histocompatibility antigen</term><term>Early stage</term><term>Glioblastoma</term><term>Loss of heterozygosity</term><term>Survival</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Perte hétérozygotie</term><term>Antigène histocompatibilité classe I</term><term>Chromosome C6</term><term>Survie</term><term>Stade précoce</term><term>Adulte</term><term>Glioblastome</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Adulte</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or β-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. Experimental Design: In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed, paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8<sup>+</sup> T-cell infiltration. Results: LOH in HLA class I, B2m, HLA class II, HLA class III, and 6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA class I expression correlated with intratumoral CD8<sup>+</sup> T-cell infiltration. Conclusion: LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests a crucial role for these genes in immunosurveillance.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><noRegion><name sortKey="Yeung, Jacky T" sort="Yeung, Jacky T" uniqKey="Yeung J" first="Jacky T." last="Yeung">Jacky T. Yeung</name></noRegion><name sortKey="Ferrone, Soldano" sort="Ferrone, Soldano" uniqKey="Ferrone S" first="Soldano" last="Ferrone">Soldano Ferrone</name><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name><name sortKey="Ikeura, Maki" sort="Ikeura, Maki" uniqKey="Ikeura M" first="Maki" last="Ikeura">Maki Ikeura</name><name sortKey="Jakacki, Regina I" sort="Jakacki, Regina I" uniqKey="Jakacki R" first="Regina I." last="Jakacki">Regina I. Jakacki</name><name sortKey="Nikiforova, Marina N" sort="Nikiforova, Marina N" uniqKey="Nikiforova M" first="Marina N." last="Nikiforova">Marina N. Nikiforova</name><name sortKey="Ohnishi, Koji" sort="Ohnishi, Koji" uniqKey="Ohnishi K" first="Koji" last="Ohnishi">Koji Ohnishi</name><name sortKey="Okada, Hideho" sort="Okada, Hideho" uniqKey="Okada H" first="Hideho" last="Okada">Hideho Okada</name><name sortKey="Okada, Hideho" sort="Okada, Hideho" uniqKey="Okada H" first="Hideho" last="Okada">Hideho Okada</name><name sortKey="Okada, Hideho" sort="Okada, Hideho" uniqKey="Okada H" first="Hideho" last="Okada">Hideho Okada</name><name sortKey="Pollack, Ian F" sort="Pollack, Ian F" uniqKey="Pollack I" first="Ian F." last="Pollack">Ian F. Pollack</name><name sortKey="Pollack, Ian F" sort="Pollack, Ian F" uniqKey="Pollack I" first="Ian F." last="Pollack">Ian F. Pollack</name><name sortKey="Potter, Douglas M" sort="Potter, Douglas M" uniqKey="Potter D" first="Douglas M." last="Potter">Douglas M. Potter</name><name sortKey="Potter, Douglas M" sort="Potter, Douglas M" uniqKey="Potter D" first="Douglas M." last="Potter">Douglas M. Potter</name><name sortKey="Potter, Douglas M" sort="Potter, Douglas M" uniqKey="Potter D" first="Douglas M." last="Potter">Douglas M. Potter</name><name sortKey="Yeung, Jacky T" sort="Yeung, Jacky T" uniqKey="Yeung J" first="Jacky T." last="Yeung">Jacky T. Yeung</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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