In a major breakthrough for ovarian and uterine cancers, Yale researchers have defined the genetic landscape of rare, highly aggressive tumors called carcinosarcomas (CSs), pointing the way to possible new treatments. The findings are published in the Oct. 10 online early edition of Proceedings of the National Academy of Sciences.
|Panel showing both epithelial and sarcomatous cells of carcinosarcoma.|
Endometrial and ovarian cancers are the most prevalent gynecologic tumors in women, with over 76,160 newly diagnosed cases and about 14,270 deaths in 2015 in the United States alone. Although carcinsarcomas comprise only 2%-5% of all uterine malignancies and 1%-2% of all ovarian tumors, they are responsible for a disproportionate number of deaths due to their high biologic aggressiveness and resistance to standard treatments, such as radiation and chemotherapy.
The collaborative research team — which included experts in gynecological cancer, genomics, pathology and computational biology– performed a comprehensive genetic analysis of ovarian and endometrial carcinosarcomas. The team collected tumors from 68 women affected with ovarian and uterine carcinosarcomas to try to determine the molecular basis of the tumor’s aggressive behavior. They sequenced all the genes from the tumors and identified mutations that are crucial for these tumors to grow. The team also studied the copy number variations — genes that are not mutated but are amplified in the tumors to give them a growth advantage over normal tissues. Results of the study show that in addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, researchers 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. Researchers 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.
“We’ve established unequivocally the common genetic origin of these tumors as epithelial tumors,” he added. “Importantly, by studying the genetics of both the carcinomatous and sarcomatous elements of these tumors, we demonstrated that the transition from carcinoma to sarcoma, which represent one of the main characteristics of these tumors, may happen at different times during the evolution of these cancers.”
Publication: Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition.
Adapted from press release by Yale University
Leave a Reply