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Research Team IDs Hundreds of Mutated Genes in Stomach Cancer

NEW YORK (GenomeWeb News) – Researchers from Duke-National University of Singapore and the National Cancer Center Singapore have conducted a large-scale exome sequencing study that turned up hundreds of genes mutated in stomach cancers.

The researchers sequenced the exomes of 15 gastric adenocarcinomas and their matched normal DNAs and have published the results of their research in the latest issue of Nature Genetics. In total, they sequenced the coding regions of around 18,000 genes using Agilent Technologies' SureSelect exome capture kits and Illumina's GAIIx or HiSeq platforms.

The researchers identified 718 non-silent somatic point mutations in 661 different genes, and using Sanger sequencing found another 30 predicted small indels in 28 genes including the tumor-suppressor genes PTEN and APC.

Investigators identified, on average, 50 non-synonymous somatic mutations for each gastric cancer, a rate they said is comparable to that found in colon and pancreatic cancer and hepatocellular carcinoma. Three mutations that have been previously observed in gastric cancer — TP53, PIK3CA, and CTNNB1 — also were present in the gastric cancer exomes in this study. The researchers also identified 26 other genes recurrently mutated in at least two of the 15 tumors.

Among the genes of particular interest to the researchers was FAT4, which displayed a greater than expected number of non-synonymous mutations, and, according to the reseahcers, provided evidence of being a tumor suppressor. The gene belongs to the E-cadherin family, which has been implicated in previous gastric cancer research.

FAT4 was recurrently mutated in around 5 percent of the tumors (six out of 110). Further, a survey of other cancers showed FAT4 nonsense and missense mutations in hepatocellular carcinoma (one out of 10 exomes), pancreatic cancer (two out of 24 exomes), and head and neck squamous cell carcinoma (two out of 32 exomes).

In addition to FAT4, the SWI/SNF-related chromatin remodeling gene ARID1A was mutated in nine out of the 110 tumors, an 8 percent rate. "This figure is lower than but nevertheless comparable to a recent study reporting a 14 percent (26/180) rate of ARID1A protein loss in gastric cancer," the study authors wrote.

They also noted that ARID1A mutations were significantly associated with tumors showing PIK3CA-activating mutations, which suggests that ARID1A inactivation may synergize with PIK3CA activation to facilitate cellular transformation and may be a key molecular pathway in gastric cancer. "Given that PI3K inhibitors are currently in clinical testing in gastric cancer, it may prove interesting to evaluate whether tumor responses to these compounds are influenced by the genomic status of ARID1A," the study authors said.

"More research is required to realize the clinical implications of these findings," Patrick Tan, an associate professor in the cancer and stem cell biology program at Duke-NUS and senior author on the study, said in a statement. "ARID1A and FAT4 are likely also involved in many other cancer types, not just stomach cancer."

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