Abstract
Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.
Highlights
Lung cancer is currently the leading cause of cancer death and second most diagnosed cancer worldwide, with an incidence of 11.4% and a mortality far higher than any other cancer types (18.0%) [1]
Based on a TCGA dataset consisting of 506 samples, we conducted an integrated analysis of the somatic mutation landscape of lung adenocarcinoma
We obtained FAT3 and LRP1B, two key genes closely related to the immunogenicity, cytotoxicity and immunotherapy response of lung adenocarcinoma patients
Summary
Lung cancer is currently the leading cause of cancer death and second most diagnosed cancer worldwide, with an incidence of 11.4% and a mortality far higher than any other cancer types (18.0%) [1]. Despite great progress have been made in the treatment of lung cancer, the five-year survival rate for patients diagnosed between 2010 and 2014 was only 10% to 20% in most countries [2]. The prevalence of lung cancer in China has been among the top for many years. In 2015, lung cancer was the most common malignancy and caused the most cancer-related deaths in China [3]. Adenocarcinoma is the most common histologic subtype of lung cancer, belonging to NSCLC [4]. Only a minority of NSCLC patients can really benefit from ICIs treatment [10]
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