Fewings E, et al. - In this whole-exome sequencing study, the researchers identified new candidate genes linked with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic E-cadherin gene (CDH1) variants. The data presented in this work showed a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. In addition, new candidate genes associated with disease risk in these families was identified.

Methods

• Researchers performed whole-exome sequencing on DNA taken from the blood of 39 people (28 people diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants.
• Using gene-interaction analysis, genes with loss-of-function variants were prioritized to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.

Results

• According to the findings, protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer.
• Variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes.
• They found a frameshift deletion in PALB2 in one member of a family with a history of gastric and breast cancer.
• Data reported that two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss.
• It was noted that one family had a unique combination of variants in the DNA repair genes ATR and NBN.
• Results revealed that two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.