Incidence of Hereditary Gastric Cancer May Be Much Higher than Reported

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.

Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer

“…To further explore this, we investigated the GTP-bound (active) state of myc-RhoA R129W in MKN1 cell lysate. In the positive control [20] lysates that were incubated with GTPγS to ensure that it irreversibly occupied the GTP/GDP binding pocket and formed constitutively active forms, both myc-RhoA and myc-RhoA R129W showed similar levels of the GTP-bound state, indicating that there is no problem with the GTP-binding ability compared to the protein expression levels. Notably, in the experimental group (NT lysates), myc-RhoA R129W has over 2.5-fold (p=0.009) higher GTPbound form than did myc-RhoA in terms of the active state (Fig.…”