Matthieu Le Gallo1, Meghan L Rudd1, Mary Ellen Urick1, Nancy F Hansen1, Suiyuan Zhang2, Fred Lozy1, Dennis C Sgroi3,4,5, August Vidal Bel6,7, Xavier Matias-Guiu7,8, Russell R Broaddus9, Karen H Lu9, Douglas A Levine10, David G Mutch11, Paul J Goodfellow12, Helga B Salvesen13,14, James C Mullikin1,15, Daphne W Bell1. 1. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 2. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 3. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts. 4. Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts. 5. Department of Pathology, Harvard Medical School, Boston, Massachusetts. 6. Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain. 7. Department of Pathology, Hospital Universitari de Bellvitge, Barcelona, Spain. 8. Department of Pathology and Molecular Genetics/Oncological Pathology Group, Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRB Lleida, Lleida, Spain. 9. Division of Surgery, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 10. Gynecologic Oncology, Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. 11. Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri. 12. Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 13. Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Bergen, Norway. 14. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. 15. National Institutes of Health Intramural Sequencing Center, National Institutes of Health, Bethesda, Maryland.
Abstract
BACKGROUND: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. METHODS: We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. RESULTS: Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). CONCLUSION: Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8.
BACKGROUND: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. METHODS: We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. RESULTS: Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). CONCLUSION: Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8.
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