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

Abstract

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring 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 frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.uterine carcinosarcoma | ovarian carcinosarcoma | exome sequencing C arcinosarcomas (CSs) of the female genital tract, also known as mixed malignant Müllerian tumors, are rare but highly aggressive tumors characterized by a biphasic histology. These cancers most commonly arise in the uterus, followed by the ovaries, fallopian tubes, and vagina (1-3). The diagnosis of CS requires the presence of both sarcomatous and carcinomatous components. Although the pathogenesis of CSs remains under debate, an increasing body of evidence supports the origin of both elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, rather than two independent progenitors (2-5).The overall 5-y survival is only 30 ± 9% for all stages, and the recurrence rate after surgery is extremely high (50-80%) (3-5). The uncertain origin and poor prognosis of uterine and ovarian CSs motivate determination of the molecular basis of CS aggressive behavior in the hope of developing novel and effective treatment modalities. ResultsThe Genetic Landscape of CS. A total of 68 patients with stage I-IV uterine (n = 44) and ovarian (n = 24) CSs were studied. Their clinical and histological features are presented in SI Appendix, Table S1. Upon surgical removal of tumors, primary cell lines were prepared (five tumors) or tumors were frozen (63 tumors). Among t...

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

“…Eight primary carcinosarcoma (CS) cell lines (cell lines characteristics, epithelial/stromal components of each cell line and tissue source are described in Table 1) were established from chemotherapy-naïve patients at the time of primary staging surgery after sterile processing of fresh tumor biopsy samples, as described previously and evaluated in our study (10,12). All revived cells were used within 50 passages, and cultured for less than 6 months.…”

“…These genetic landscape results are consistent with previous clinical/pathological studies showing that the epithelial component of the carcinosarcoma drives the growth and proliferation of these rare and biologically aggressive gynecologic cancers. Because of the reported overexpression and/or gene amplification of HER2 in over one third of uterine serous carcinoma (12, 13) which represents the high grade epithelial component of a large number of gynecologic CS (10), HER2 may represent an attractive target for anticancer therapy (4). …”

ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference

“…By extension, perturbation of this region of the nucleosome through either aberrant PTM installation or mutation could lead to dysregulation of epigenetic processes. Indeed, a mutation in the acidic patch (H2AE56Q) has recently been implicated in human uterine and ovarian carcinomas 30 .…”

Response to pembrolizumab in a heavily treated patient with metastatic ovarian carcinosarcoma

“…OCS most frequently contains high-grade serous components, which often contain a TP53 mutation, and the precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a TP53 signature [13]. Given the poor response of OCS to standard available therapies, researchers have sought insight from molecular characterizations such as next-generation whole-exome sequencing [14]. Unsurprisingly, given the high rate of serous adenomatous components in OCS, the most common alteration is in TP53 [13].…”

“…Other alterations described include mutations in H2A and H2B , deletions of TP53 and MBD3 , and amplification of chromosome segments containing PIK3CA , TERT , and MYC . However, few of these mutations are directly druggable [14]. …”