Identification of shared neoantigens in BRCA1-related breast cancer

Abstract

Personalized neoantigen-based cancer vaccine has been shown to be safe and immunogenic in cancer patients; however, the manufacturing process can be costly and brings about delay in treatment. Using off-the-shelf cancer vaccine by targeting shared neoantigen may circumvent these problems. We identified BRCA1-mutated breast cancer as a candidate for shared neoantigens because of its clinical aggressiveness and its genotypic and phenotypic similarities suggesting common somatic mutational events within the group. Therefore, we hypothesized that shared-neoantigen may be identified among BRCA1-related breast cancer and may be used as targets for shared neoantigen vaccine. For analyses, we obtained genome sequencing data of breast cancer samples with or without somatic BRCA1 mutations (BRCA1-positive and BRCA1-negative, respectively) from the 3 public cancer databases; The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Catalogue of Somatic Mutations in Cancer (COSMIC). We found that SNVs were the dominant mutation type with C>T being the most abundant SNV type found in both BRCA1-positive and -negative groups. The most frequently mutated genes were TP53 and TTN in BRCA1-positive and PIK3CA and TP53 in BRCA1-negative samples. Total variant counts, the number of SNVs and indels were higher in BRCA1-positive than -negative group. As for shared neoantigens, we found PIK3CA H1047R, E545K, E542K and N345K recurrently in BRCA1-negative groups across all databases, whereas BRCA1-positive groups were inconclusive. We analyzed samples with known germline BRCA1 mutations for shared neoantigens and found that TP53 R175H was the most frequent mutation but was not found among top somatic mutations in BRCA1-positive or -negative samples. Most of the top neoantigens identified in BRCA1-negative samples were not found in BRCA1-positive or germline BRCA1 samples. Our findings reflected different mutational consequences between somatic and germline BRCA1 breast cancers and should be further investigated.