Incidence of Hereditary Gastric Cancer May Be Much Higher than Reported

SIMPLE SUMMARY: Hereditary gastric cancer is supposed to be a rare condition and depends on the presence of a recognized pathogenic mutation. Nonetheless, many cases fulfill the clinical criteria for HGC but lack those mutations. This report suggests new mutations to be included as putatively involved in HGC risk. A hypothesis of genetic ancestry influencing the identification of HGC mutations is sustained, since never-reported mutations were revealed to occur in Amerindians and, mainly, in admixed populations with a significant Amerindians genetic background, suffering early-onset gastric cancer. These populations are under-represented in international data banks of cancer mutations, and these newly reported mutations may pave the way for incorporating additional lab tests to discover HGC, favoring early diagnosis and risk-reduction procedures, improving clinical outcomes, and contributing to HGC control. ABSTRACT: Hereditary gastric cancers (HGCs) are supposed to be rare and difficult to identify. Nonetheless, many cases of young patients with gastric cancer (GC) fulfill the clinical criteria for considering this diagnosis but do not present the defined pathogenic mutations necessary to meet a formal diagnosis of HGC. Moreover, GC in young people is a challenging medical situation due to the usual aggressiveness of such cases and the potential risk for their relatives when related to a germline variant. Aiming to identify additional germline alterations that might contribute to the early onset of GC, a complete exome sequence of blood samples from 95 GC patients under 50 and 94 blood samples from non-cancer patients was performed and compared in this study. The number of identified germline mutations in GC patients was found to be much higher than that from individuals without a cancer diagnosis. Specifically, the number of high functional impact mutations, including those affecting genes involved in medical diseases, cancer hallmark genes, and DNA replication and repair processes, was much higher, strengthening the hypothesis of the potential causal role of such mutations in hereditary cancers. Conversely, classically related HGC mutations were not found and the number of mutations in genes in the CDH1 pathway was not found to be relevant among the young GC patients, reinforcing the hypothesis that existing alternative germline contributions favor the early onset of GC. The LILRB1 gene variants, absent in the world’s cancer datasets but present in high frequencies among the studied GC patients, may represent essential cancer variants specific to the Amerindian ancestry’s contributions. Identifying non-reported GC variants, potentially originating from under-studied populations, may pave the way for additional discoveries and translations to clinical interventions for GC management. The newly proposed approaches may reduce the discrepancy between clinically suspected and molecularly proven hereditary GC and shed light on similar inconsistencies among other cancer types. Additionally, the results of this study may support the development of new blood tests for evaluating cancer risk that can be used in clinical practice, helping physicians make decisions about strategies for surveillance and risk-reduction interventions.