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Gastric Cancer Cases Frequently Harbor Genetic Risk Variants, Suggesting Germline Testing

NEW YORK – Findings from a retrospective genetic analysis of esophagogastric cancer cases suggest that germline mutations in cancer-related genes may be more common than previously appreciated, particularly for individuals with gastric cancer.

For a paper published in JAMA Network Open on Monday, researchers at Memorial Sloan Kettering Cancer Center (MSK) and elsewhere analyzed MSK-IMPACT panel sequence data on tumor-normal samples from 515 individuals with esophagogastric cancer, identifying likely pathogenic or pathogenic germline alterations in more than 80 patients. The germline variants included mutations in moderate- and high-penetrance cancer risk genes such as BRCA1, BRCA2, ATM, CDH1, and MSH2.

But the germline risk variants were not uniform across the cases, the team reported. While nearly 20 percent of patients with gastric cancer had likely pathogenic or pathogenic variants in their germline samples, such alterations turned up in germline sequences from just over 14 percent of individuals with gastroesophageal junction, or GEJ, cancer and nearly 11 percent of esophageal cancer patients.

A similar pattern held for risk variants in cancer-related genes considered moderate- to high-penetrance, the team noted. Pathogenic or likely pathogenic variants in those genes turned up in 29 of the 243 gastric cancer cases profiled but just eight of the 111 esophageal cancer cases.

Cancer-related germline variants were also overrepresented in patients diagnosed under age 50, the researchers reported, suggesting that they may contribute to early-onset forms of esophagogastric cancer.

"This large retrospective analysis suggests that pathogenic germline variants may be significantly more common in gastric than in esophageal cancer, with GEJ tumors having an intermediate prevalence," co-senior authors Zsofia Stadler and Yelena Janjigian, both researchers at MSK, and their co-authors reported. They added that such variants were also more common in patients with esophagogastric cancer diagnosed at or before age 50, "although this observation was of borderline significance and needs to be validated."

Together, the team argued, such results point to a potential need for expanding germline testing beyond suspected inherited cancer syndrome cases, particularly since more than three-quarters of the individuals included in the study — and more than 55 percent of those with risk variants in moderate- or high-penetrance genes — did not meet existing clinical guidelines for germline testing based on their personal or family history.

"Given the inadequate sensitivity of existing clinical guidelines, as well as barriers to access to genetic evaluation, this study suggests that any patient with gastric cancer in the US who undergoes somatic tumor genetic testing should also undergo germline testing," the authors wrote, adding that the results of such testing could impact screening recommendations for family members of gastric cancer patients.

The investigators did not find evidence for more robust platinum chemotherapy responses in esophagogastric cancer patients carrying germline variants in BRCA1/2 or other genes in homologous recombination or DNA damage repair pathways, though they cautioned that the analysis may have been underpowered to detect such differences.

In an accompanying commentary in JAMA Network Open, Fox Chase Cancer Center clinical genetics researcher Michael Hall and colleagues called the effort "an important contribution to our understanding of how germline variants co-segregate with the diagnosis of [esophagogastric cancer]."

With regard to universal germline testing for gastrointestinal cancer patients, though, they warned that the panel test may uncover germline variants that inform some patients' risk of other cancer types without necessarily explaining why they developed esophagogastric cancer or guiding treatment strategies.

"If an argument for universal testing is improved cancer treatment, it should also be appreciated that none of the variants identified in the current study have immediate implications for [esophagogastric cancer] treatment selection beyond off-label uses or clinical trial eligibility, aside from the small number of patients … with likely high microsatellite instability gastric cancer with MSH2 variants for whom anti-programmed cell death 1 ligand therapy is relevant," the researchers noted, adding that "patients with early-stage disease may conceivably benefit from knowledge of germline variants associated with future cancer risk."