Gastric adenocarcinoma (GA) is considered a major cause of death in patients with primary antibody deficiencies (PAD). The risk of developing GA was found to be 5-16 times higher in CVID patients than in the general population, with the mean age at diagnosis being significantly younger. Importantly, a monogenic origin has been identified in less than 10% of CVID patients and it is currently thought that most cases have a polygenic origin.
Whole-Exome/Genome Sequencing (WES/WGS) opens new opportunities to study the genetic background of PAD and to identify variants that perturb pathways relevant for the development of GA in these individuals.
We generated the WES profile of 41 PAD patients, including 9 patients (5F/4M) with GA (median age at diagnosis: 45 (27-62)). We then performed genome-wide studies to identify differences that might explain this increased oncogenic risk, by comparing these 9 patients with healthy individuals and the remainder of the PAD cohort.
We identified 394 potentially deleterious variants (CADD>15) with an allele frequency below 0.05 (GNOMAD NFE population), with none of these being present in the top 20 genes with somatic mutations associated with GA (Cosmic database). Exome-wide association demonstrates that PAD patients with GA have 368 variants with significantly higher frequency than healthy controls. The pathways associated with the identified genes are currently under investigation.
This first analysis of the exome of a cohort of primary antibody deficiency patients focused on gastric adenocarcinoma identified germline variants that may explain mechanisms underlying their susceptibility to this particular malignancy.