The purpose of this study is to describe two Chilean families having Hereditary Gastric Cancer (GC). Both families present variants of uncertain significance (VUS), that could be pathogenic, but show incomplete penetrance. GC is the leading cause of cancer-related death in Chile. Worldwide, about ten percent of gastric cancer have a familial aggregation and in Hereditary Diffuse Gastric Cancer (HDGC), E-Cadherine 1 gene (CDH1) and alpha-E-catenin gene (CTNNA1) are the most commonly mutated genes. To our knowledge, only one HDGC Chilean family with a pathogenic CDH1 mutation has been reported, suggesting a low frequency of CDH1 mutations in this population. The index patient of the first family had a diffuse GC at age 59-y. His father and paternal grandfather also died of GC. A CDH1 germline variant c.88C>A in (p.Pro30Thr, rs139866691) was found previously in the index patient by Sanger sequencing. Variant genotyping in available family members showed that two non-affected sisters were carriers. In the second family, there were eleven members affected with GC and two with breast cancer. The index patient was diagnosed with a tubular/intestinal gastric tumor at 51y of age and had a brother who died of GC at 38y. Cancer gene panel sequencing was performed in index patient DNA and cascade genotyping in family members was performed using Kompetitive allele-specific PCR. A germline variant c.293G>A (p.R98Q, rs746832629) in the CTNNA1 gene was found in the index patient. We searched the variant in other members of the family and carried out a co-segregation analysis, that indicates an incomplete penetrance of the variant because two non-affected brothers do have it. Additionally, one affected sister did not carry the variant, but her tumor sample´s histology is papillary, the most frequent type in sporadic CG and her age of onset was 60-y. Both rs139866691 and rs746832629 are located in conserved structures of their coding proteins. rs139866691 maps to a conserved loop in the E-Cadherin 1 preprotein domain and rs746832629 maps to the first alpha-helix of alpha-E-catenin corresponding to the beta-catenin binding domain. Based on our data, we believe that both variants are likely pathogenic and causative of the hereditary GC observed in these families but show incomplete penetrance. To search for additional candidate pathogenic variants, we recently completed whole-exome sequencing in the index cases from the two available affected cases of the second family and we found other candidate genes reported in breast cancer and related with nitroso compound metabolism. We are searching for the second hit in the second family index patient´s tumor sample and performing isogenic models and functional analysis of rs139866691 and rs746832629 to clarify their pathogenicity.

Citation Format: Graciela Molina, Carol Parra, Nicole B Halmai, Ana P Estrada, Alma Poceros, Paul Lott, Rasika Venkatesh, Enrique Norero, Osvaldo Torres, Alejandro Corvalán, Luis Carvajal-Carmona. CDH1 and CTNNA1 variants with incomplete penetrance in hereditary gastric cancer Chilean families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5899.