Whole-Exome Sequencing Illuminates DNA Damage in Uterine Serous Carcinoma

Exome sequencing is an efficient strategy to selectively sequence the coding regions of the genome, and as such, it is a cheaper but still effective alternative to whole genome sequencing. Exons are short, functionally important sequences of DNA which represent the regions in genes that are translated into protein and the untranslated region (UTR) flanking them. UTRs are usually not included in exome studies. In the human genome, there are about 180,000 exons: these constitute about 1% of the human genome. It is estimated that the protein coding regions of the human genome constitute about 85% of the disease-causing mutations.

Results published in the January 28, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) revealed that that 52 USC tumors had fewer than 100 (median 36) somatic mutations, whereas five had more than 3,000. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, there was a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD–chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance.

These findings identified frequent mutations due to DNA damage that effected chromatin remodeling as well as cell cycle and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.

"We have clearly identified the mutations that are responsible for USC tumors," said senior author Dr. Alessandro Santin, professor of obstetrics, gynecology, and reproductive sciences at Yale University. "In addition to a number of well-known cancer genes, we found three genes that had not previously been associated with cancer that are found in these tumors. This finding points to new pathways that could be important in developing therapies down the road."

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