Common cancer-driver mutations and their association with abnormally methylated genes in lung adenocarcinoma from never-smokers. (September 2018)

• Record Type: Journal Article
• Authors: Tessema, Mathewos; Rossi, Michael R.; Picchi, Maria A.; Yingling, Christin M.; Lin, Yong; Ramalingam, Suresh S.; Belinsky, Steven A.
• Is Part Of: Lung cancer. Volume 123(2018)
• Page Start: 99
• Page End: 106
• Publication Date: 2018-09
• Subjects: Lung adenocarcinoma -- Non-smokers -- Mutation -- Methylation; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2018.07.011
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Lung adenocarcinoma in never smokers is a growing health concern in many countries. Some targetable cancer driver mutations like EGFR are more common in these tumors. Mutation of 20 cancer driver genes was screened in 112 tumors and compared with cancer-related methylation of 59 genes. EGFR mutation is the most prevalent found in 40% of these tumors. Methylation of many genes is significantly more common in EGFR wild type tumors. Abstract: Objectives: Lung adenocarcinoma in never-smokers accounts for 15–20% of all lung cancer. Although targetable mutations are more prevalent in these tumors, the biological and clinical importance of coexisting and/or mutually exclusive abnormalities is just emerging. This study evaluates the relationships between common genetic and epigenetic aberrations in these tumors. Materials and methods: Next-generation sequencing was employed to screen 20 commonly mutated cancer-driver genes in 112 lung adenocarcinomas from never-smokers. The relationship of these mutations with cancer-related methylation of 59 genes, and geographical/ethnic differences in the prevalence for mutations compared to multiple East Asian never-smoker lung adenocarcinoma cohorts was studied. Results: The most common driver mutation detected in 40% (45/112) of the tumors was EGFR, followed by TP53 (18%), SETD2 (11%), and SMARCA4 (11%). Over 72% (81/112) of the cases have mutation of at least one driver gene. While 30% (34/112) of the tumors have co-mutations of two or more genes, 42% (47/112) have only one driver gene mutation. Differences in the prevalence for some of these mutations were seen between adenocarcinomas in East Asian versus US (mainly Caucasian) never-smokers including a significantly lower rate of EGFR mutation among the US patients. Interestingly, aberrant methylation of multiple cancer-related genes was significantly associated with EGFR wildtype tumors. Among 15 differentially methylated genes by EGFR mutation, 14 were more commonly methylated in EGFR wildtype compared to mutant tumors. These findings were independently validated using publicly available data. Conclusion: Most lung adenocarcinomas from never-smokers harbor targetable mutation/co-mutations. In the absence of EGFR mutation that drives 40% of these tumors, EGFR wildtype tumors appear to develop by acquiring aberrant promoter methylation that silences tumor-suppressor genes.