Increased Rates of Occult Signet Ring Cell Gastric Cancer Seen in CDH1 P/LP Variant Carriers

Prospective data found higher rates of occult signet ring cell gastric cancer among individuals with no family history of gastric cancer but who carried CDH1 P/LP variants.

High rates of occult signet ring cell gastric cancer were observed among carriers of CDH1 P/LP variants who had no family history of gastric cancer and were diagnosed with hereditary lobular breast cancer (HLBC), according to results from a prospective cohort study published in JAMA Surgery.

Occult signet ring cell carcinoma was observed in 11 of 32 patients with HLBC who underwent 1 or more surveillance endoscopies. Moreover, 15 of 16 patients who underwent total gastrectomy harbored gastric adenocarcinoma. Further, 43.3% of patients in the hereditary diffuse gastric cancer (HDGC) group who underwent surveillance had occult carcinoma, and 94.7% of had occult gastric cancer at the time of gastrectomy.

“We have shown that occult gastric adenocarcinoma is highly prevalent in families with [HLBC and] CDH1 variants. These data support the claim that the risk of occult gastric cancer remains high for patients with HLBC irrespective of family history,” the investigators wrote.

The study enrolled individuals between October 2017 and January 2021 who carried a CDH1 variant. Data included gastric and breast pathological findings, demographic characteristics, CDH1 genotype, and family pedigrees. Patients enrolled self-reported sex, and race and ethnicity.

The study association analyses were divided according to breast cancer family history and no gastric cancer in the HLBC group; gastric cancer family history and no breast cancer in the HDGC group; and both breast and gastric cancer family history in the mixed group.

A total of 283 patients withCDH1 P/LP variants were included in the research. Median age was 48 years in the overall population, and most patients from this population were female (70.3%) and White (91.5%). Personal breast cancer history was noted in 20.4% of patients and gastric cancer was in 2% of patients. In total, 15.5% of patients were in the HLBC group, 16.2% were in the HDGC group, and 68.2% were in the mixed group.

After examining 151 families, 455 relatives were diagnosed with breast cancer and 466 relatives received a diagnosis of gastric cancer. Of note, most variants were nonsense variants (32%) that were distributed across all CDH1 domains.

The investigators explained that the study, which focused on a hereditary cancer syndrome, was limited by ascertainment bias, even with a larger sample size. The separation of patients based on the strength or weakness of cancer history may have also produced different results, according to the investigators.

“It is paramount that patients previously assigned a diagnosis of HLBC are not excluded from receiving a proper gastric cancer risk assessment and counseling. The mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the investigators concluded.


Gamble LA, Rossi A, Fasaye GA, et al. Association between hereditary lobular breast cancer due to CDH1 variants and gastric cancer risk. JAMA Surg. 2022;157(1):18-22. doi:10.1001/jamasurg.2021.5118