Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing

Abstract

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.

Next-generation sequencing in the clinic: Promises and challenges

“…Currently, three major commercial products including Agilent's Sure-Select (array-based and solution-based), Nimblegen's SeqCap (array-based and solution-based) and Illumina's TruSeq (solution-based) in conjunction with NGS platforms have been proven highly effective in exome sequencing [50,51]. Thus far, a number of studies have reported the identification of causal mutations by exome sequencing for many genetic diseases [52,53] and cancers [54][55][56][57][58][59][60][61][62][63] (Table 2). …”

Detecting the potential cancer association or metastasis by multi-omics data analysis

“…Interestingly, a recent study has found that CSMD3 is the second most frequently mutated gene (next to TP53) in lung cancer. This study demonstrated that loss of CSMD3 might be causative for increased proliferation of airway epithelial cells (Liu et al, 2012). The finding of a significant number of somatic mutations in the LRP1B gene is not simply a result of of its long coding region; recently published cancer genome studies have also found its potential association with glioblastoma (GBM) and lung adenocarcinoma (Lawrence et al, 2013).…”

Whole exome sequencing for cancer – is there evidence of clinical utility?

“…All the studies presented in this table used the Agilent SureSelect platform for exome enrichment, followed by the use of Illumina platforms (either Genome Analyzer II or HiSeq [Illumina Inc.]) for sequencing. The two non-small cell-lung carcinoma studies showed differences in the variant type, based on the subtype of the cancer; 33,34 for example, the ratio of nonsynonymous to synonymous variants was nominally statistically significantly higher in adenocarcinoma patients compared with squamous cell carcinoma patients (3.6 versus 2.8; P=0.05). 33 Follow-up of potential candidate genes identified .15 genes in all studies, [33][34][35] with some genes having a highly significant proportion of variants (P range; 2×10…”

“…Lung-related cancers WES studies in lung cancers have been conducted for non-small-cell lung carcinoma (two studies) 33,34 and lung adenocarcinoma (one study). 35 These studies are described in Table 5.…”

“…33 weS in other types of cancer WES studies have been conducted in other types of cancers, including colon and colorectal cancer, 36,37 prostate cancer, 38,39 and head and neck squamous cell carcinoma. 40,41 Since the methodology and criteria used to evaluate the results are similar to those described previously (ie, include assessment of the genotype landscape and, in some cases, identification of potential candidate genes to be further evaluated), these studies are not described in this review.…”