Molecular subtyping and prognostic assessment based on tumor mutation burden in patients with lung adenocarcinomas

Abstract

Tumor mutation burden (TMB) is a potential biomarker for response to immunotherapy.The subset of patients with TMB has not been well characterized in lung adenocarcinomas. Here we performed molecular subtyping based on TMB and compared the features of different subtypes including clinical features, somatic driver genes and mutational signatures. We found that patients with lower tumor mutation burden had a longer disease-free survival, while higher tumor mutation burden is associated with smoking and aging. Analysis of somatic driver genes and mutational signatures demonstrates a significant association between somatic RYR2 mutations and the subtype with higher mutation burden. Overall, our study identified two molecular subtypes based on TMB and described the corresponding difference in their clinical and genomic levels.

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

“…Cimas et al found that mutation in RYR2 was associated with favorable outcome in basal-like breast tumors expressing PD-1/PD-L1 [22]. Wang et al reported that RYR2 mutation was a signi cant biomarker for suggesting high TMB in lung adenocarcinoma [26]. In this study, we found that RYR2 mutation was an independent protective prognostic factor, and had a positive relationship with high TMB in EAC.…”

“…RYR2 is a major component of the intracellular Ca 2+ release channels and is associated with the endoplasmic or sarcoplasmic reticulum of several cell types, especially in cardiomyocytes [20,21]. Recent studies demonstrated that RYR2 was signi cantly mutated in multiple cancers, and RYR2 was reported to be a driver gene in cervical cancer, colon cancer, breast cancer, head and neck cancer, and lung adenocarcinoma [22][23][24][25][26]. Femi et al demonstrated that mutation in RYR2 was a prognosis biomarker of cervical cancer and breast cancer [27].…”

The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

“…In this way, the efficacy of EGFR‐TKIs might decrease due to the decreased exposure in smokers than never‐smokers. What is more, the tumour mutation burden was negatively correlated with the efficacy of EGFR‐TKI 33 while smoking displays a strong correlation with increased tumour mutational burden 34,35 . In this way, the efficacy of EGFR‐TKI might decrease in smoking patients.…”

Neoantigen Load as a Prognostic and Predictive Marker for Stage II/III Non-Small Cell Lung Cancer in Chinese Patients

“…Speci cally, tumor neoantigens have been de ned as peptides that are derived from somatic gene mutations and express in tumor cells but not in normal cells that can be recognized by tumor-in ltrating lymphocytes (TILs) [43]; thus, NAL is an ideal surrogate of immunogenicity. Indeed, a high NAL number was able to predict response of cancer patients to the immune checkpoint blockade (ICB)immunotherapy [44], while detection of the neoantigen-MHC complex rather than mutated genes could help to initiate the anti-tumor immune response [45] and frequent recognition of neoantigens by CD4+ T cells occurred in human melanoma [46]. Moreover, various mutation types contributed to different neoantigen productions; for example, the probability of the indels that altered a given gene open-reading frame could generate a neo-antigen was three folds higher than that of non-synonymous SNV [47]; thus, use of NAL number to predict DFS could be much better than TMB numbers.…”