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Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli ( APC ) gene. Carriers with mutations in the  APC  gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the  APC  gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35–60 years) carrying this mutation. The remaining four members (6–23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated  in silico  for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPept VAC . A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8 +  T cells isolated from either an FAP + / APC mut  individual, or from a FAP - / APC mut  individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP - / APC wt ) or from healthy unrelated donors, showed a robust response, suggesting that CD8 +  T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported  APC  gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic  APC  gene mutations to delay/treat colorectal cancer.

A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity