Abstract 800: A germline CTNNA1 variant in a large Chilean family with hereditary diffuse gastric cancer

Abstract

Abstract The purpose of this study is to describe a large Chilean family having a Hereditary Diffuse Gastric Cancer and a possible causative mutation of cancer in this family. Gastric cancer is the leading cause of cancer-related death in Chile. Worldwide, only ten percent of gastric cancer have a familial aggregation and in Hereditary Diffuse Gastric Cancer (HDGC), E-Cadherine 1 gene (CDH1) is the most commonly mutated gene (30%). 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. CTNNA1 mutations (alpha-1 catenin gene), also have been found in HDGC cases. E-cadherine 1 and alpha-1 catenin are part of adherens junction complex. In this family, there are eleven members affected with gastric cancer and two with breast cancer, in two following generations. The index patient was diagnosed with a diffuse gastric tumor at 51 years of age and one affected relative (a deceased brother of the index case) at 38 years of age. The index patient´s gastric tumor histology type is diffuse, but the tumor of the affected sister is papillary. 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. This variant has been reported two times in ClinVar and is classified as an uncertain significance variant. In TCGA, CTNNA1 c.293G>A variant has been reported four times in gastric, colon, and uterine tumor samples. This variant maps to the beta-catenin binding domain of the protein, and the mutated residue is conserved from fish to primates. The variant population frequency in the Genome Aggregation Database is in Latinos is 0.0049 and worldwide is 0.000076. 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. Based on our data, we think that this variant could be pathogenic and causative of the HDGC observed in this family, but showing an incomplete penetrance. Additionally, the variant was not found in sixty-two other early-onset Chilean cancer gastric patients, thus we are going to search the variant in a sample of the general population of the family´s region. Also, we will do a whole-exome sequence in the samples of all available affected relatives looking for other variants to explain the incomplete penetrance, search for the second hit in an index patient´s tumor sample and perform a functional analysis of the variant during this semester. Beca Chile Postdoctorado 74190063, CONICYT-FONDAP 15130011-2 (NIH). Citation Format: Graciela Molina, Ana Estrada, Alma Poceros, Carol Parra, Osvaldo Torres, Natalia Landeros, Andrés Rodríguez, Alejandro Corvalán, Luis Carvajal-Carmona. A germline CTNNA1 variant in a large Chilean family with hereditary diffuse gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 800.