Genetic Analysis May Lead to Improved Clinical Trials for Uterine Carcinosarcoma

It may soon be possible to create more specific and targeted clinical trials for uterine carcinosarcoma (UCS) tumors. Researchers at the NYU Langone Medical Center’s Perlmutter Cancer Center have discovered multiple somatic mutations and copy-number alterations in UCS tumors that offer expanded therapeutic options, including potential use of PARP, EZH2, cell cycle, and PI3K pathway inhibitors.  

In a study published March 13, 2017, in Cancer Cell, they report on an integrated genomic, epigenomic, transcriptomic, and proteomic analysis of UCS tumors. The researchers found that while all UCS tumors share some genetic traits, there is great diversity among the tumors. Instead of having a few commonly mutated genes, UCS tumors were found to have mutations in genes that play a wider variety of roles in cancer biology than previously thought. 

“The biggest surprise was the genetic variety within tumors of this type,” said lead study author Douglas Levine, MD, director of the Division of Gynecologic Oncology at NYU Langone Medical Center’s Perlmutter Cancer Center in New York.

Using this new collection of genomic information it was possible to trace the molecular roots of UCS to create a “new genetic atlas” for the disease. Levine said clinicians now will be better able to determine the specific genetic fingerprint of each patient’s tumor and subsequently find treatment options that better suit them. Levine said this search for new options is urgently needed because only about one of every three women survives longer than 5 years after diagnosis with a UCS tumor.

The researchers analyzed tissue samples from 57 women with confirmed cases of UCS, and found 64% had their cancer recur within the study follow-up period and 58% died. The average follow-up period was 25.7 months.

Analysis of the 57 samples yielded 60,000 individual characteristics, which then were narrowed down to 9,149 genetic mutations. The researchers used this information and combined it with clinical data about UCS and studies of other related cancers. They identified five genes most commonly associated with UCS (PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS). The team also discovered a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases. This gene signature was attributable to epigenetic alterations at microRNA promoters.

Interesting to note was that while the p53 normally protects against cancer, this gene was mutated in 91% of the tumors in the study.

The team compared the UCS tumor samples to data on other cancers in The Cancer Genome Atlas of the National Cancer Institute and the National Human Genome Research Institute. Levine said comparing traits of UCS tumors to these large databases revealed that UCS tumors may be related at the molecular level to entirely different kinds of cancer.

It is now hoped that this better understanding of morphologic components of both epithelial and mesenchymal cell types may lead to new treatment approaches. The authors note that the newly recognized EMT features may provide a mechanistic basis for targeting endometrial carcinoma precursors.