A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity
| Autor: | Sakthivel Murugan, Arati Khanna-Gupta, Vedam L. Ramprasad, Yogesh Mistry, Papia Chakraborty, Priyanka Shah, Ravi Gupta, Snigdha Majumder, Bharti Mittal, Lakshmi Mahadevan, Jisha Elias, Rakshit Shah, Jason K. D’Silva, Karunakaran Coral, Anand Kumar Maurya, Rekha Sathian, Amitabha Chaudhuri |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Physiology Colorectal cancer lcsh:Medicine Gene mutation medicine.disease_cause Biochemistry Germline Database and Informatics Methods Epitopes 0302 clinical medicine Animal Cells Immune Physiology Medicine and Health Sciences lcsh:Science Mutation Immune System Proteins Multidisciplinary High-Throughput Nucleotide Sequencing Pedigree Oncology Adenomatous Polyposis Coli 030220 oncology & carcinogenesis White blood cells Female Cellular Types Colorectal Neoplasms Research Article Adult Blood cells Heterozygote Genes APC Adenomatous polyposis coli Immune Cells Immunology Adenomatous Polyposis Coli Protein T cells Antigen-Presenting Cells Cytotoxic T cells Biology Research and Analysis Methods Familial adenomatous polyposis 03 medical and health sciences Germline mutation Genetics medicine Humans Antigens Germ-Line Mutation Colorectal Cancer lcsh:R Biology and Life Sciences Proteins Cancers and Neoplasms Cancer Cell Biology medicine.disease digestive system diseases Biological Databases 030104 developmental biology Mutation Databases biology.protein Cancer research Somatic Mutation lcsh:Q Peptides |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 9, p e0203845 (2018) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0203845 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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