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Diverse Alterations Detected In Rare, Aggressive Uterine Cancer

NEW YORK (GenomeWeb) – A new, integrated omics study has uncovered an unexpectedly diverse set of molecular processes that can go awry in a rare and aggressive form of gynecological cancer called uterine carcinosarcoma.

"The biggest surprise was the genetic variety within tumors of this type," co-corresponding author Douglas Levine, gynecologic oncology director at the New York University Langone Medical Center's Laura and Isaac Perlmutter Cancer Center, said in a statement, noting that "we can [now] apply what we've learned to creating more specific clinical trials."

Levine led a team of researchers from NYU, the University of Texas MD Anderson Cancer Center, and other centers in the US and Canada, who used a combination of genomic, epigenomic, and proteomic profiling approaches to characterize samples from 57 untreated women with uterine carcinosarcoma. Their findings, published online today in Cancer Cell, highlighted some of the genes and pathways that are recurrently altered in the disease, including the TP53 tumor suppressor gene, which was mutated in most of the tumors tested.

The team's tumor transcriptome sequences suggested some uterine carcinosarcomas — particularly those with epigenetic shifts in the promoters of microRNAs — tend to show a so-called epithelial to mesenchymal transition, producing tumors that are particularly tricky to treat. Even so, the level of this shift varied dramatically across the full set of uterine carcinosarcomas considered.

The researchers' analyses focused on samples from 57 women with uterine carcinosarcoma, who had an average age of 70 years. More than half of the study participants died over an average follow-up time of just over two years, they noted, and 64 percent experienced cancer recurrence.

Using exome sequencing, genotyping arrays, methylation arrays, RNA sequencing, and/or reverse-phase protein arrays, the team profiled somatic protein-coding mutations, copy number changes, transcriptional patterns, miRNA expression, methylation marks, and proteomic patterns in the tumors.

On the somatic mutation side, for example, the researchers identified more than 9,100 mutations. At the gene level, such mutations were over-represented in the TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS genes, they reported — a situation that resembles that previously described in other gynecological cancer types such as endometrioid and serous uterine carcinomas.

Similarly, the team's proteomic analysis uncovered features described in past studies of gynecological cancers or in other forms of sarcoma, though the proteomic data did not lead to distinct uterine carcinosarcoma subtypes.

On the other hand, the available expression data pointed to a wide range of epithelial-to mesenchymal transition signatures in the uterine carcinosarcomas. The epithelial-to mesenchymal transition features also appeared to coincide with changes in the promoter methylation and expression of some miRNAs, including members of the miR-200 family. 

"The array of targets identified in this study provides compelling opportunities to develop molecularly driven clinical trials to individualize and improve cancer care for primary and recurrent [uterine carcinosarcomas]," the authors concluded. "Combined with its rarity, the diverse molecular landscape of [uterine carcinosarcoma] tumors supports clinical trials in cooperative groups to develop independent treatment paradigms."

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