Abstract
Approximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA). We confirm that the mutations in MSI Colon Cancers are frequently frameshift deletions (23% in MSI; 1% in microsatellite stable), We find that these mutations cluster at specific locations in the genome which are mutated in up to 41% of the patients. We filter these for an adequate variant allele frequency, a sufficient mean mRNA level and the formation of a Super Neo Open Reading Frame (SNORF). Finally, we check the influence of Nonsense Mediated Decay (MMD) by comparing RNA and DNA sequencing results. Thereby we identify a set of 20 NMD-escaping Public FPs (PFPs) that cover over 90% of MSI Colon, 62.2% of MSI Endometrial and 58.8% of MSI Stomach cancer patients and 3 out of 4 Lynch patients in the TCGA-COAD. This underlines the potential for PFP directed immunotherapy, both in a therapeutic and a prophylactic setting in multiple types of MSI cancers.
Highlights
Protein products derived from mutated regions of DNA are a source of neo-antigens that can drive immune activation against cancer and convey susceptibility to immunotherapy [1,2,3,4]
In general Microsatellite Instable (MSI) colon cancer patients have a higher mutational burden than microsatellite stable (MSS) colon cancer patients (MSI: median = 2974, n = 71; MSS: median = 218, n = 272; p < 0.0001) (Fig 2A) and a larger percentage of their mutations consists of deletions or insertions (MSI: single nucleotide polymorphisms (SNPs) = 72%, INDELS are frameshift mutations (INS) = 5%, DEL = 23%’; MSS: SNP = 97%, INS 1%, DEL = 1%) (Fig 2B)
Based on DNA and RNA sequencing data from MSI colon cancer patients in the TGCA we identified a subset of frameshift mutations that cluster to distinct coding microsatellites (cMS) in the genome, produce super NORFS (SNORFS) that evade Nonsense Mediated Decay (NMD), and have sufficient length for presentation in MHC context
Summary
Protein products derived from mutated regions of DNA are a source of neo-antigens that can drive immune activation against cancer and convey susceptibility to immunotherapy [1,2,3,4]. INDELS in coding DNA result in frameshifted RNA containing neo open reading frames (NORFS) that, once translated, give rise to completely non-self, out-offrame protein products. These out-of-frame proteins can be degraded into peptides and presented in the context of multiple MHC alleles.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
