Recurrent Neoantigens in Colorectal Cancer as Potential Immunotherapy Targets

Abstract

This study was aimed to investigate the mutations in colorectal cancer (CRC) for recurrent neoantigen identification. A total of 1,779 samples with whole exome sequencing (WES) data were obtained from 7 published CRC cohorts. Common HLA genotypes were used to predict the probability of neoantigens at high frequency mutants in the dataset. Based on the WES data, we not only obtained the most comprehensive CRC mutation landscape so far, but also found 1550 mutation sites which could be identified in at least 5 or more patients, including KRAS G12D (8%), KRAS G12V (5.8%), PIK3CA E545K (3.5%), PIK3CA H1047R (2.5%) and BMPR2 N583Tfs*44 (2.8%). These mutations can also be recognized by multiple common HLA molecules as potential 'public' neoantigens. Many of these mutations also have high mutation rates in metastatic pan-cancers, suggesting their value as therapeutic targets in different cancer types. Overall, our analysis provides recurrent neoantigens as potential cancer immunotherapy targets.

A Comprehensive Survey of Mutations in Oesophageal Carcinoma Reveals Recurrent Neoantigens as Potential Immunotherapy Targets

“…PIK3CA H1047R mutation is most commonly in breast cancer [29] and is also hot spots in multiple cancer types in the MSK-impact cohort [30]. Our previous studies have shown that this mutation is a potential neoantigen in patients with gastric cancer and colorectal cancer [14,21]. Combined with the results of this study and previous studies, we suggest that this mutation may be a potential immunotherapeutic target for patients with gastrointestinal tumors.…”

“…For neoantigen prediction, a total of 43 HLA-I genotypes and 8 HLA-II genotypes were selected for neoantigen affinity and presentation probability assessment as previously reported ( Supplementary Table S2) [14]. Mutations, which include 214 non-silent somatic SNVs and 39 indels, could be identified in at least 3 patients.…”

“…This different mutation pattern may suggest that the carcinogenic mechanisms are different in EC patients carrying mutations in these genes. It's worth noting that the mutual exclusion of PIK3CA and TP53 also exists in colorectal cancer and gastric cancer [14,23,24], indicating that this may be a common feature of digestive system cancer. There are many hot spot mutations in EC samples.…”

“…KRAS Gly12 (including G12V, G12C, and G12D) is a classic cancer mutation in multiple cancers including endometrial, colorectal cancer, and non-small cell lung cancer [30]. We previously reported high frequency mutations and high frequency neoantigens of G12D/V in gastric and colorectal cancer [14,31], our research group also demonstrated by mass spectrometry recently that KRAS G12V mutated neoantigen can be presented by HLA-A11:01 cell lines [32]. Previous studies have shown that gastrointestinal tumors, including esophageal cancer, gastric cancer, colon cancer and rectal cancer, have some similarities in tumor tissue origin and molecular characteristics [33], which are also reflected in this study, and high-frequency neoantigens in esophageal cancer are also similar to gastric cancer and colorectal cancer, suggesting the universality of neoantigen-based immunotherapy in gastrointestinal tumors.…”

Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

“…28,32 Although mutations in RAS have been associated with immune exclusion, 33 certain dominant oncogenic mutations of KRAS, such as G12D and G12V, may be associated with SNV-derived neoantigens. 34 T-cell immunogenicity has been reported for epitopes derived from these RAS mutations, 35 and immunization with these peptides can generate CD8 and CD4 T-cell responses. 36,37 RAS-specific adoptive cell therapy leading to tumor regression has also been reported.…”