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Mutational Landscape of Uterine and Ovarian Carcinosarcomas Implicates Histone Genes in Epithelial–Mesenchymal Transition

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Mutational Landscape of Uterine and Ovarian Carcinosarcomas Implicates Histone Genes in Epithelial–Mesenchymal Transition Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition Siming Zhaoa,b, Stefania Bellonec, Salvatore Lopezc, Durga Thakrala,b, Carlton Schwabc, Diana P. Englishc, Jonathan Blackc, Emiliano Coccoc, Jungmin Choia,b, Luca Zammataroc, Federica Predolinic, Elena Bonazzolic, Mark Bia,b, Natalia Buzad, Pei Huid, Serena Wongd, Maysa Abu-Khalafe, Antonella Ravaggif, Eliana Bignottif, Elisabetta Bandieraf, Chiara Romanif, Paola Todeschinif, Renata Tassif, Laura Zanottif, Franco Odicinof, Sergio Pecorellif, Carla Donzellig, Laura Ardighierig, Fabio Facchettig, Marcella Falchettig, Dan-Arin Silasic, Elena Ratnerc, Masoud Azodic, Peter E. Schwartzc, Shrikant Manea,b, Roberto Angiolih, Corrado Terranovah, Charles Matthew Quicki, Babak Edrakij, Kaya Bilgüvara,b, Moses Leek, Murim Choik, Amy L. Stieglerl, Titus J. Boggonl, Joseph Schlessingerl, Richard P. Liftona,b,m,1, and Alessandro D. Santinc aDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510; bHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; cDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; dDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06510; eInternal Medicine & Oncology, Yale University School of Medicine, New Haven, CT 06510; f“Angelo Nocivelli” Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy; gDepartment of Pathology, University of Brescia, 25100 Brescia, Italy; hDivision of Gynecologic Oncology, Universita’ Campus Bio-Medico di Roma, 00128 Rome, Italy, iDepartment of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; jDivision of Gynecologic Oncology, John Muir Health Clinical Research Center, Concord, CA 94598; kDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea; lDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06510; and mLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065 Contributed by Richard P. Lifton, August 25, 2016 (sent for review January 5, 2016; reviewed by Michael J. Birrer and Elise Kohn) Carcinosarcomas (CSs) of the uterus and ovary are highly aggres- The overall 5-y survival is only 30 ± 9% for all stages, and the sive neoplasms containing both carcinomatous and sarcomatous recurrence rate after surgery is extremely high (50–80%) (3–5). elements. We analyzed the mutational landscape of 68 uterine and The uncertain origin and poor prognosis of uterine and ovarian ovarian CSs by whole-exome sequencing. We also performed CSs motivate determination of the molecular basis of CS ag- multiregion whole-exome sequencing comprising two carcinoma gressive behavior in the hope of developing novel and effective and sarcoma samples from six tumors to resolve their evolutionary treatment modalities. histories. The results demonstrated that carcinomatous and sarco- Results matous elements derive from a common precursor having muta- – tions typical of carcinomas. In addition to mutations in cancer genes The Genetic Landscape of CS. A total of 68 patients with stage I IV TP53 uterine (n = 44) and ovarian (n = 24) CSs were studied. Their previously identified in uterine and ovarian carcinomas such as , SI Appendix PIK3CA, PPP2R1A, KRAS, PTEN, CHD4,andBCOR, we found an ex- clinical and histological features are presented in , cess of mutations in genes encoding histone H2A and H2B, as well Table S1. Upon surgical removal of tumors, primary cell lines as significant amplification of the segment of chromosome 6p har- were prepared (five tumors) or tumors were frozen (63 tumors). Among these tumors, 41 had matched normal tissues available boring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and Significance frequent amplification of chromosome segments containing the genes PIK3CA, TERT,andMYC. Stable transgenic expression of Some cancers, termed carcinosarcomas (CSs), have mixed cell H2A and H2B in a uterine serous carcinoma cell line demonstrated types, with either epithelial or mesenchymal features. Sequenc- that mutant, but not wild-type, histones increased expression of ing the genomes of uterine and ovarian CSs demonstrated that markers of epithelial–mesenchymal transition (EMT) as well as tu- these different cell types derive from a common precursor cell mor migratory and invasive properties, suggesting a role in sarcoma- that has many mutations typical of epithelial cancers. In addi- tous transformation. Comparison of the phylogenetic relationships tion, we find that these tumors have a significant burden of of carcinomatous and sarcomatous elements of the same tumors point mutations and amplification of histone genes, suggesting demonstrated separate lineages leading to these two components. a potential role of these mutations in sarcomatous trans- These findings define the genetic landscape of CSs and suggest ther- formation. Consistent with this finding, expression of specific apeutic targets for these highly aggressive neoplasms. histone gene mutations in uterine carcinoma cells changed gene expression toward a mesenchymal state. These findings have uterine carcinosarcoma | ovarian carcinosarcoma | exome sequencing potential implications for the treatment of these cancers. Author contributions: J.S., R.P.L., and A.D.S. designed research; S.B., D.T., D.P.E., J.B., E.C., arcinosarcomas (CSs) of the female genital tract, also known F.P., E. Bonazzoli, N.B., P.H., S.W., A.R., E. Bignotti, E. Bandiera, C.R., P.T., R.T., L. Zanotti, Cas mixed malignant Müllerian tumors, are rare but highly C.D., L.A., F.F., and M.F. performed research; S.L., C.S., J.C., L. Zammataro, M.A.-K., F.O., aggressive tumors characterized by a biphasic histology. These S.P., D.-A.S., E.R., M.A., P.E.S., S.M., R.A., C.T., C.M.Q., B.E., K.B., and M.L. contributed new cancers most commonly arise in the uterus, followed by the reagents/analytic tools; S.Z., M.B., M.C., A.L.S., T.J.B., R.P.L., and A.D.S. analyzed data; and S.Z., A.L.S., T.J.B., J.S., R.P.L., and A.D.S. wrote the paper. ovaries, fallopian tubes, and vagina (1–3). The diagnosis of CS Reviewers: M.J.B., Massachusetts General Hospital/Harvard Medical School; and E.K., Na- requires the presence of both sarcomatous and carcinomatous tional Institutes of Health. components. Although the pathogenesis of CSs remains under The authors declare no conflict of interest. debate, an increasing body of evidence supports the origin of Freely available online through the PNAS open access option. both elements from a common epithelial cell that undergoes 1To whom correspondence should be addressed. Email: [email protected]. sarcomatous dedifferentiation, rather than two independent This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. progenitors (2–5). 1073/pnas.1614120113/-/DCSupplemental. 12238–12243 | PNAS | October 25, 2016 | vol. 113 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1614120113 Downloaded by guest on October 1, 2021 and tumor-normal pairs were subjected to whole-exome se- mutations in the tumor suppressors TP53 (tumor protein P53) and quencing, with 197 mean reads per targeted base for tumor PTEN (phosphatase and tensin homolog). All of these genes have samples and 101 for normal tissues; 94.5% of the targeted bases been previously implicated in uterine and/or ovarian carcinomas. had at least 20 independent sequence reads (SI Appendix, Table In addition, we identified two tumors with a previously un- S2). Tumor purity was estimated from the minor allele frequency identified somatic mutation in HIST1H2AB [G > Catchromo- of somatic mutations and segments showing loss of heterozy- some 6 (chr6): 26033628; amino acid change, E57Q]. HIST1H2AB gosity (LOH) or copy number variation (CNV); the mean tumor encodes the histone H2A protein type 1-B/E. This gene has not purity was 81%. Somatic point mutations were identified using previously been implicated in cancer, and this variant was absent MuTect (6) for normal-tumor pairs and were further filtered to from public and Yale University databases. The probability of reduce false-positive calls (Materials and Methods). Somatic having any recurrent G:C > C:G mutation in this dataset by indels were called by in-house Perl scripts (Materials and Meth- chance, given the size of the exome, the number of tumors, and ods). For unmatched tumors, we first called variants from the the observed substitution-specific mutation rate (0.5 per megabase reference sequence and then excluded variants that have a fre- pair), was low (P < 0.01). − quency higher than 2 × 10 5 in the Exome Aggregation Con- To identify genes with an increased burden of somatic mutation, sortium (ExAC) database (7). Driver mutations were confirmed we used MutSigCV (12) to analyze all somatic damaging muta- by manual inspection of the reads plot, and selected mutations tions (premature termination, splice site, and indel mutations) as were confirmed by Sanger sequencing. well as missense mutations at phylogenetically conserved sites in In total, 4,115 somatic point mutations (3,056 protein-altering the 37 matched tumors (Materials and Methods). With a genome- mutations) and 49 indels from the 41 matched normal-tumor wide false discovery
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