Mutational signal in gastric CA might open new therapeutic avenues

Last Updated: 2015-11-04

By Will Boggs MD

NEW YORK (Reuters Health) - A mutational signal associated with failure of double-strand DNA break repair is present in about one in 10 gastric cancers, researchers report.

"There was no prior evidence for failure of DNA double-strand break-repair in gastric cancer, and it was quite surprising to see that approximately 10% of these cancers harbor a DNA-repair deficiency," Dr. Ludmil B. Alexandrov from Wellcome Trust Sanger Institute in Cambridgeshire, U.K., told Reuters Health.

A specific base substitution signature ("signature 3") is present in cancers harboring germline and/or somatic mutations in BRCA1 and BRCA2 and other genes, but the prevalence of this signature has not been reported for gastric cancers.

Dr. Alexandrov's multinational team investigated the presence of signature 3 in 10,250 pairs of cancer-normal samples derived from 36 distinct types of human cancer.

As expected from previous work, the researchers found signature 3 in ovarian, breast, and pancreatic cancers.

But among 33 other cancers derived from diverse epithelial, mesenchymal, glial, hematopoietic, and lymphoid cells, only gastric cancer showed signature 3.

Signature 3 was present in 7.3% of whole-exome gastric samples and 12.0% of whole-genome gastric samples, the researchers report in Nature Communications, online October 20.

Gastric cancers with signature 3 mutations had other mutational hallmarks of failure of homology-directed double-strand break repair despite the absence of inactivating mutations in BRCA1 and BRCA2 genes.

Gastric samples with signature 3 were enriched for intestinal type histology and had a tendency to display a "growth in cell suspension" pattern.

Signature 3 was not present in any of the 20 gastric cell lines the investigators analyzed.

"This result may lead to a less toxic and more effective therapy for gastric cancer," Dr. Alexandrov said. "Cancers with signature 3 will be most likely susceptible to platinum drugs as well as to the less toxic PARP inhibitors."

"Our results are only based on laboratory/scientific study," Dr. Alexandrov cautioned. "Further clinical trials employing signature 3 will be needed to confirm the applicability of precision medicine based on mutational signatures."

SOURCE: http://bit.ly/1HqwJSA

Nat Commun 2015.