Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

Abstract

BackgroundLung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted.MethodsWe analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis.ResultsWe identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001).ConclusionsThe genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer

“…Recurrent mutations in CDH10 have recently been reported in EGFR/KRAS/ALK mutation-negative lung adenocarcinoma in never-smokers [25] and as a prognostic mutation signature in colorectal cancer [26]. Our study indicated that CDH10 is not only the most commonly and significantly mutated gene in SCLC but also associated with poor survival in SCLC.…”

Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

“…It has been found to be mutated in lung adenocarcinoma negative for mutations in EGFR/KRAS/ALK [31]. …”

Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer

“…Other genes with deleterious mutations in ≥3 primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, FAM135B, HGF, AR, BAI3, EP300, KDR, PAPPA2, PDGRRA and RUNX1 . Several of those genes, such as ATM [7], MLL3 [42], and SETD2 [6,43], were recently reported to be frequently mutated/changed in lung cancers, suggesting that their mutations may be used as biomarkers for these cancers. A number of large genes included in the analysis, such as CSDM3, CSDM1, HYDIN , LRP2, LRP1B, PCLO, and RYR2, most of them encoding proteins with >4000 amino acids, were also found to have high mutation frequencies.…”

“…Whether those EGFR mutations contribute to tumorigenesis or sensitize cancers to anti-EGFR therapy remains to be determined. Several genes, such as ATM [7], MLL3 [42], and SETD2 [6,43], were recently reported to be frequently mutated/changed in lung cancers. In addition, several large genes that were included in the analysis, such as CSDM3, CSDM1, HYDIN , LRP2, LRP1B, PCLO, and RYR2, were also found to be frequently mutated in our lung cancer samples.…”