YALE CRITERIA FOR GENETIC TESTING IN CASES OF SUSPECTED HEREDITARY DIFFUSE GASTRIC CANCER (HDGC) ARE MORE SENSITIVE THAN IGCLC AND ERN GENTURIS CRITERIA IN A LARGE AMERICAN COHORT

Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome characterized by early-onset diffuse gastric cancer (DGC) and lobular breast cancer (LBC). This syndrome is most often caused by pathogenic variants in the CDH1 gene. The International Gastric Cancer Linkage Consortium (IGCLC) developed clinical criteria for genetic testing in cases of suspected HDGC and updated them most recently in 2020. Our group previously showed these criteria to have poor sensitivity and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) subsequently proposed expanding the IGCLC criteria and showed its “lobular breast cancer-expanded” criteria to be more sensitive than the IGCLC criteria in a European cohort of CDH1 mutation carriers. The purpose of this study was to compare performance of the ERN GENTURIS criteria with the IGCLC’s and our Yale criteria in a large American cohort of CDH1 mutation carriers.

Methods: Medical histories of 860 CDH1 mutation carriers, identified predominantly by multigene panel testing at three US commercial laboratories, and their 4993 family members were reviewed. The percentage of subjects fulfilling the IGCLC criteria, the ERN GENTURIS criteria, and our Yale criteria were calculated. We made these calculations under two different conditions: first making no assumptions about unavailable pathology, then assuming gastric cancers in probands with confirmed CDH1 mutations to be diffuse when pathology was unavailable.

Results: When making no assumptions about unavailable pathology, the Yale criteria had a sensitivity of 68.6% for CDH1 pathogenic variants, compared with 15.0% and 27.1% for the IGCLC and ERN GENTURIS criteria, respectively. When assuming gastric cancers in probands with confirmed CDH1 mutations to be diffuse, sensitivities were 72.2%, 21.6%, and 33.6% for the Yale, IGCLC, and ERN GENTURIS criteria, respectively.

Conclusions: In our cohort, which is the largest reported to date, the IGCLC and ERN GENTURIS criteria only called for genetic testing in a small minority of CDH1 pathogenic variant carriers, while the Yale criteria detected a large majority. Identifying these individuals is important, as current guidelines call for prophylactic total gastrectomy or annual gastric surveillance in all CDH1 mutation carriers. Capturing the full phenotypic spectrum of CDH1 pathogenic variants is also crucial for developing appropriate guidance for patients with this condition. In addition to having superior sensitivity, our Yale criteria have the major advantages of not relying heavily on pathology information from family members (as it is rarely available) and taking into consideration recommendations generated by other cancer genetics guidelines, addressing important practical issues encountered in cancer genetics clinics.