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PLoS One. 2018 Sep 26;13(9):e0203845. doi: 10.1371/journal.pone.0203845. eCollection 2018.

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

Author information

1
MedGenome Labs Pvt. Ltd., Bangalore, India.
2
KCHRC, Muni Seva Ashram, Goraj, Gujarat, India.
3
MedGenome Inc., Foster City, CA, United States of America.

Abstract

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, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) 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.

PMID:
30256815
PMCID:
PMC6157866
DOI:
10.1371/journal.pone.0203845
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The following authors are employed by MedGenome Labs Pvt. Ltd., MedGenome Inc: SMajumder, JE, KC, PS, AKM, BM, JKD, SMurugan, LM, RS, VR, PC, RG, AC and AK-G, and have no additional commercial affiliation relating to employment, consultancy, patents, products in development, or marketed products. Our commercial affiliation with MedGenome Labs does not alter adherence to all PLOS ONE policies on sharing data and materials. We declare that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

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