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Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.

ABSTRACT: PURPOSE:The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear. EXPERIMENTAL DESIGN:We genotyped 3,026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical, and smoking history data. RESULTS:EGFR mutations were found in 43% of never smokers and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of never smokers. In patients with smoking histories up to 10 pack-years, EGFR predominated over KRAS. Among former smokers with lung cancer, multivariate analysis showed that, independent of pack-years, increasing smoking-free years raise the likelihood of EGFR mutation. Never smokers were more likely than smokers to have KRAS G > A transition mutation (mostly G12D; 58% vs. 20%, P = 0.0001). KRAS G12C, the most common G > T transversion mutation in smokers, was more frequent in women (P = 0.007) and these women were younger than men with the same mutation (median 65 vs. 69, P = 0.0008) and had smoked less. CONCLUSIONS:The distinct types of KRAS mutations in smokers versus never smokers suggest that most KRAS-mutant lung cancers in never smokers are not due to second-hand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history together support a heightened susceptibility to tobacco carcinogens.

SUBMITTER: Dogan S

PROVIDER: S-EPMC3500422 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.

Dogan Snjezana S Shen Ronglai R Ang Daphne C DC Johnson Melissa L ML D'Angelo Sandra P SP Paik Paul K PK Brzostowski Edyta B EB Riely Gregory J GJ Kris Mark G MG Zakowski Maureen F MF Ladanyi Marc M

Clinical cancer research : an official journal of the American Association for Cancer Research 20120926 22

<h4>Purpose</h4>The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear.<h4>Experimental design</h4>We genotyped 3,026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical, and smoking history data.<h4>Results</h4>EGFR mutations were found in 43% of never smokers and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of never smokers. In patien ...[more]

PMID: 23014527

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Project description:Epidermal growth factor receptor EGFR major driver mutations may affect downstream molecular networks and pathways, which would influence treatment outcomes of non-small cell lung cancer (NSCLC). This study aimed to unveil profiles of mutant proteins expressed in lung adenocarcinomas of 36 patients harboring representative driver EGFR mutations (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Surprisingly, the orthogonal partial least squares discriminant analysis performed for identified mutant proteins demonstrated the profound differences in distance among the different EGFR mutation groups, suggesting that cancer cells harboring L858R or Ex19del emerge from cellular origins different from L858R/Ex19del-negative cells. Weighted gene coexpression network analysis, together with over-representative analysis, identified 18 coexpressed modules and their eigen proteins. Pathways enriched differentially for both the L858R and Ex19del mutations included carboxylic acid metabolic process, cell cycle, developmental biology, cellular responses to stress, mitotic prophase, cell proliferation, growth, epithelial to mesenchymal transition (EMT), and immune system. The IPA causal network analysis identified the highly activated networks of PARPBP, HOXA1, and APH1 under the L858R mutation, whereas those of ASGR1, APEX1, BUB1, and MAPK10 were highly activated under the Ex19del mutation. Interestingly, the downregulated causal network of osimertinib intervention showed the highest significance in overlap p-value among most causal networks predicted under the L858R mutation. We also identified the causal network of MAPK interacting serine/threonine kinase 1/2 (MNK1/2) highly activated differentially under the L858R mutation. Tumor-suppressor AMOT, a component of the Hippo pathways, was highly inhibited commonly under both L858R and Ex19del mutations. Our results could identify disease-related protein molecular networks from the landscape of single amino acid variants. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

Dataset Information

Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.

Publications

Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.

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