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Mutational Signature Points to Possibility of Targeted Treatment for Some Stomach Cancers

NEW YORK (GenomeWeb) – A team from the UK, US, and Hong Kong has uncovered a mutational signature in some stomach cancer genomes that is expected to coincide with response to targeted, DNA-damaging treatments used in other cancer types.

The signature — marked by specific DNA base substitutions — appears to stem from mutations affecting BRCA1, BRCA2, and/or other genes involved in homologous recombination-based DNA repair pathways, making tumors more prone to apoptosis in the face of additional DNA damage.

The researchers identified this so-called signature 3 mutation pattern in some 7 to 12 percent of gastric tumors when they analyzed more than 10,000 tumors that had been tested by exome or genome sequencing. The work, published online this week in Nature Communications, also detected higher-than-anticipated proportions of breast, ovarian, and pancreatic tumors containing this mutational signature.

Because these signature 3-containing breast, ovarian, and pancreatic cancers are more likely to respond to DNA-damaging drugs such as platinum-based chemotherapy and PARP inhibitors, the team noted that the results suggest that a subset of gastric cancers may also respond to such treatments.

"In years to come, routine genomic analysis of cancers could show which have the signature 3 fingerprint and inform and transform treatment of thousands of patients with these specific breast, ovarian, pancreatic and gastric cancers," senior author Michael Stratton, director of the Wellcome Trust Sanger Institute, said in a statement.

For the analysis, Stratton and his colleagues brought together exome sequences for 9,643 tumor-normal samples and sequences from another 607 tumor-normal pairs tested by whole-genome sequencing. Together, the samples represented three-dozen different cancer types, including 372 gastric cancers assessed by exome sequencing and 100 whole-genome gastric cancer sequences.

As reported in the past, the team discovered signature 3 mutations in a significant proportion of the breast, ovarian, and pancreatic tumors.

The signature turned up in nearly 31 percent of the 466 ovarian tumors considered, as well as almost 27 percent of 1,051 exome-sequenced breast cancers and more than 29 percent of breast cancers for which whole-genome sequences were available.

Within the set of 15 pancreatic cancers tested by whole-genome sequencing, some 40 percent contained the signature, the researchers reported, likely reflecting the intentional enrichment for tumors containing BRCA1 and/or BRCA2 mutations.

On the other hand, they found the signature in just over 7 percent of the randomly sampled collection of 216 pancreatic cancers that had been tested by whole-genome sequencing.

Across the remaining 33 cancer types included in the study, the team saw signature 3 tumors in just one: gastric cancer. There, the signature turned up in 7.3 percent of 27 sequenced exomes and 12 percent of the 12 whole-genome sequenced gastric cancers.

Even so, the signature was not restricted to tumors with BRCA mutations, the researchers explained, suggesting it might be possible to expand the proportion of breast, ovarian, pancreatic, and, now, gastric tumors treated with platinum therapy and/or PARP inhibitors.

"While all the patients with BRCA1 and BRCA2 mutations show this signature 3 fingerprint, there are also many patients who have signature 3 but don't have mutations in BRCA1 and BRCA2," co-author Suet Yi Leung, a pathology researcher and gastrointestinal cancer genetics and genomics chair at the University of Hong Kong, said in a statement.  

"By focusing exclusively on those two genes, clinicians may be missing many cancer patients with the genomic signature 3 who could benefit from PARP inhibitor drugs or platinum therapy," Leung added.

The team cautioned that further work is needed to look at targeted treatment responses and clinical outcomes in gastric cancer cases marked by signature 3 mutations.