Identifying Neoantigens Resulting from Frameshift, Somatic Mutations in the Tumor Suppressor Gene, APC for Colorectal Cancer Vaccine Design

Abstract:

Colorectal cancer is a debilitating disease driven by many unique mutations. One frequently mutated gene is Adenomatous Polyposis Coli (APC). The APC gene encodes a protein that is essential for the destruction of (Beta)-catenin, the effector protein of the WNT signaling pathway that regulates cell proliferation. Loss-of-function (LOF) alleles in APC result in the inability to degrade (Beta)-catenin, permitting (Beta)-catenin entry into the nucleus to complex with TCF/LEF transcription factors, which upregulates mitotic genes. There are numerous ways in which APC LOF alleles might arise, including point mutations that result in missense or nonsense consequences as well insertion or deletion mutations that yield frameshifts. In the latter case, a premature stop codon is typically encountered. Truncation can yield a neoantigen peptide sequence (>11 amino acids) that may be sufficient to activate the host immune system. Utilizing a Catalogue of Somatic Mutations in Cancer (COSMIC) filter to yield high-confidence oncogenic driver alleles, we carefully mapped all 179 known frameshift lesions of APC obtained from colorectal cancer biopsies, as documented in The Cancer Genome Atlas (TCGA). Each frameshift allele is first mapped to its genomic coordinates using Ensembl Archive, followed by a predicted neoantigen frameshift consequence using NCBI CCDS (Consensus Coding Sequence). Most frameshift alleles prematurely truncate APC to roughly half its original peptide size. Neoantigens greater than 11 amino acids can be presented natively via host MHC-I alleles. We identify roughly four consensus regions amenable to cancer vaccine design due to shared immunogen sequences in resulting neoantigens.