Association of RYR2 Mutation with Tumor Mutation Burden, Prognosis and Antitumor Immunity in Patients with Esophageal Adenocarcinoma

Abstract

BackgroundEsophageal adenocarcinoma (EAC) remains a leading cause of cancer-related deaths worldwide, and demonstrates a predominant rising incidence in Western countries. Recently, immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in EAC thus far been limited to a small fraction of patients. MethodsUsing somatic mutations data of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), we delineated somatic mutation landscape of EAC patients from US and England. Bioinformatics algorithms were utilized to perform function annotation, immune cell infiltration analysis, and immunotherapy response assessment.ResultsWe found that RYR2 was a common frequently mutated gene (FMG) in both cohorts, and patients with RYR2 mutation suggested higher tumor mutation burden (TMB), better prognosis, and superior expression of immune checkpoints. Moreover, RYR2 mutation upregulated the signaling pathways implicated in immune response and enhanced antitumor immunity in EAC. Multiple bioinformatics algorithms for assessing immunotherapy response demonstrated that patients with RYR2 mutation might benefit more from immunotherapy. In order to provide additional reference for antitumor therapy of different RYR2 status, we identified nine latent antitumor drugs associated with RYR2 status in EAC. ConclusionsThis study reveals a novel gene whose mutation could be served as a potential biomarker for prognosis, TMB, and immunotherapy of EAC patients.

Mutations in lysine methyltransferase 2C and PEG3 are associated with tumor mutation burden, prognosis, and antitumor immunity in pancreatic adenocarcinoma patients

“…In addition to causing mutation-derived neoantigens, a high TMB can make tumors more immunogenic by inducing a T-cell-mediated immune response and releasing new antigens. [30][31][32][33] Therefore, we hypothesize that KMT2C and PEG3 mutations result in a higher TMB level in PAAD, activating the immune system to attack cancer. 34 During the progression of metastatic epithelial cancer, antigen mutations have recently been found in peripheral blood samples from patients with KMT2C mutations.…”

“…In addition to causing mutation-derived neoantigens, a high TMB can make tumors more immunogenic by inducing a T-cell-mediated immune response and releasing new antigens. 30–33 Therefore, we hypothesize that KMT2C and PEG3 mutations result in a higher TMB level in PAAD, activating the immune system to attack cancer. 34…”

Comprehensive Analysis of Genomic and Expression Data Identified Potential Markers for Predicting Prognosis and Immune Response in CRC

“…Wei et al found that RYR2 3′UTR polymorphisms remained significant in the genetic susceptibility of progesterone receptor positive breast cancer [25]. Liu et al found the RYR2 mutation was linked to a greater TMB and a better clinical outcome by enhancing the antitumor immune response in breast cancer and esophageal adenocarcinoma [26]. In nonsmall cell lung cancer, RYR2 mutation may prolong survival via downregulation of DKK1 and upregulation [27].…”

RYR2mutation in non‐small cell lung cancer prolongs survival via down‐regulation ofDKK1and up‐regulation ofGS1‐115G20.1: A weighted gene Co‐expression network analysis and risk prognostic models

“…Schmitt, K et al found differential promoter methylation status and expression level of RYR2 in head and neck tumor, suggesting that reduced expression of RYR2 in adjacent tissues and precancerous lesions may potentially indicate poor survival and impending malignancy [6]. In oesophageal cancer, the RYR2 mutation upregulated signalling pathways involved in the immune response and enhanced anti-tumor immunity [12]. The RYR2 rs12594 mutation (occurring in the 3 0 -UTR) also significantly reduced the risk of developing breast cancer [13].…”