Researchers find genes behind aggressive ovarian and endometrial carcinosarcomas.

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.
DOI: http://dx.doi.org/10.1073/pnas.1614120113
Adapted from press release by Yale University

Genetic targets in Colorectal Cancer: role of KRAS, MEK and TAK1 genes Identified.

Researchers from Boston University School of Medicine have discovered a possible strategy to treat colon cancers that are caused by the mutant KRAS gene, which is responsible for approximately half of all colon cancer cases. The findings, which appear online in the journal Molecular Cancer Research, may lead to better therapeutic agents to treat this disease.

Colon cancer is the third leading cause of cancer-related deaths in the U.S. Routine screenings by undergoing a colonoscopy have helped reduce mortality rates if the disease advances to malignancy, it can be very difficult to treat. Cancers with the KRAS gene mutation respond poorly to currently available therapeutic agents.

“Our study provides a new strategy to treat colon cancers driven by the mutant KRAS gene, which is based on targeting additional genes that cooperate with KRAS to promote tumor growth. These additional genes, notably MEK and TAK1, can be blocked by selective therapeutic agents to suppress colon cancer cellular proliferation and viability,” explained corresponding author Anurag Singh, PhD, assistant professor of pharmacology & experimental therapeutics at BUSM. The researchers tested 40 colon cancer cell lines that were derived from human colon cancer samples for sensitivity to inhibitors of MEK and TAK1.

They found that treating those cell lines with MEK and TAK1 inhibitors suppressed the growth of mutant KRAS-driven colon cancer cells significantly as compared to the control group. “With this study we have uncovered a novel pathway in a subset of colon cancers driven by mutant KRAS gene activation, representing an important axis of vulnerability with the potential to selectively treat these types of tumors in the clinic,” he added.

Press Release: Researchers investigate new strategy to block growth of colon cancer cells