Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Abstract

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/ Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRDchromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.endometrial carcinoma | uterine serous papillary cancer | cancer genomics E ndometrial cancer is the most prevalent gynecologic tumor in women, with an annual incidence of 47,130 new cases and 8,010 deaths in 2012 in the United States (1). On the basis of clinical and histopathological features, endometrial cancer is classified into type I and type II disease groups (2). Type I tumors, which constitute the majority of cases, are generally diagnosed at an early stage, are low grade and endometrioid in histology, are associated with a history of hyperestrogenism, and typically have a good prognosis. In contrast, type II cancers are poorly differentiated, often with serous papillary [uterine serous carcinoma (USC)] or clear cell histology. Although these tumors account for a minority of endometrial cancers, the majority of relapses and deaths occur in this group of patients (2).Among type II cancers, USC represents the most biologically aggressive subtype (3, 4). Classically, the neoplastic epithelium is characterized by serous differentiation with psammoma bodies and a predominantly papillary architecture (3). Pleomorphic cytology with nuclear atypia, prominent nucleoli, a vescicular chromatin pattern, and high mitotic activity are seen. Clinically, USC has a propensity for early intra-abdominal and lymphatic spread (3) and is more commonly diagnosed in women of African ancestry (3-5). The overall 5-y survival of USC is only 30 ± 9% for all stages, and the recurre...

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

“…Mutation spectrum analysis revealed a paucity of transversion mutations in the high-mutation group, a signature often observed in mismatch repair-deficient tumors. Mutation rates, mutation spectra, and the fraction of genome affected by CNV among the remaining 37 tumors were similar to those numbers previously reported for uterine and ovarian carcinomas (8)(9)(10).…”

“…The results identified eight genes with recurrent somatic missense mutations (Table 1). These mutations included known activating mutations in the oncogenes PIK3CA (PI3-kinase subunit alpha) and KRAS (Kirsten rat sarcoma viral oncogene homolog), a recurrent mutation in PPP2R1A (phosphatase 2a regulatory subunit) that causes loss of normal regulation of serine-threonine phosphatase 2a (11), a known recurrent mutation (N1459S) in BCOR (BCL6 corepressor) that is likely gain of function (8), and a known recurrent mutation in CHD4 (DNA helicase) (9). There were also known recurrent mutations in the tumor suppressors TP53 (tumor protein P53) and PTEN (phosphatase and tensin homolog).…”

“…S3A). Comparator carcinomas were 92 USCs [46 from our previous study (9) and 46 from the TCGA database (8)], 104 uterine endometrioid carcinomas (8), and 316 ovarian serous carcinomas (10). We found similarities in the frequency of all driver mutations in CSs and these epithelial tumors.…”

“…Among the rest of root driver mutations, we found one PIK3CA activating mutation (E542K), three PIK3R1 mutations (two indels and one missense mutation at a conserved site), and one CHD4 indel. These three genes are frequently mutated in uterine and ovarian carcinomas (8)(9)(10)27) but have rarely been seen in sarcomas (28) (SI Appendix, Table S6). This finding suggests that CS likely begins as carcinoma, followed by sarcomatous transformation.…”

POLE mutations as an alternative pathway for microsatellite instability in endometrial cancer: Implications for Lynch syndrome testing

“…Yet, in a separate study, POLE EDMs were detected in 9% of uterine serous carcinomas and were all associated with an ultramutator phenotype. 8 Unlike previous reports, in the study by Billingsworth et al, POLE mutations were identified both in cancers with MSS and in those with MSI; of the 306 tumors with MSS, 18 (5.9%) harbored POLE mutations, and 12 of the 229 tumors with MSI had POLE mutations (5.2%). Although POLE mutations were significantly more common in MSI tumors that lacked MLH1 methylation, the authors reported 4 tumors with both POLE mutations and MLH1 silencing; this was an unexpected finding, because previous reports have suggested that MLH1 silencing and POLE EDMs are mutually exclusive.…”