A large team of researchers from UC Davis and several European and Latin American institutions have identified genetic variations that contribute to familial gastric cancer. These inherited mutations, which affect the PALB2, BRCA1 and RAD51C genes and have been implicated in other cancer types, impair a critical DNA repair mechanism called homologous recombination. These findings could improve preventive care, as well as provide targets for new therapies.

The study was published in the journal Gastroenterology.

“This is a pathway that repairs DNA when it breaks,” said Luis Carvajal–Carmona, associate professor at the UC Davis Genome Center and principal investigator. “Patients with deficiencies in this pathway begin to accumulate chromosomal abnormalities that can lead to cancer.”

Prior to this study, researchers had identified a single gene associated with familial gastric cancer called CDH1. However, some families that showed increased susceptibility to these tumors lacked the CDH1 mutation. To some degree, this study helps solve that mystery by identifying new genetic culprits. PALB2, BRCA1 and RAD51C play critical roles in the cell cycle, repairing double–stranded DNA breaks.

“The discovery of this pathway could be important for prevention,” said Carvajal–Carmona. “These genes should be considered when a patient presents with a gastric cancer family history.”

To identify these mutations, the team sequenced DNA from blood samples from 28 CDH1–negative patients with hereditary diffuse gastric cancer (HDGC) and found two patients with PALB2 variations and one with a RAD51C mutation. Later, they analyzed samples from 333 additional patients (both HDGC and sporadic gastric cancer) and found 11 with mutations in PALB2, BRCA1 and RAD51C. Of the HDGC patients, 6.5 percent had mutations in these genes.

During the study, the researchers were careful to rule out other possible contributors, such as H. pylori infection or smoking. This culling process confirmed that these mutations likely caused the cancers.

In addition to helping identify patients who may be at higher risk for gastric cancer, these findings may also provide a therapeutic strategy. A relatively new class of drugs that inhibit the PARP protein may hold promise for some gastric cancer patients.

“There are only two molecularly–guided therapies for gastric cancer approved by the FDA,” Carvajal–Carmona said. “However, tumors with homologous recombination deficiencies, like the ones we found in these patients, could be eligible for treatment with PARP inhibitors in clinical trials.”

Though this study breaks new ground identifying new genes associated with familial gastric cancer, Carvajal–Carmona warns that it’s a small sample and more work must be done.

“We hope that this study will stimulate the scientific community to look at CDH1–negative patients to establish the prevalence of these other mutations and to learn more about the clinical and genetic characteristics of this syndrome.”