Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS -Mutant Cancers

Dogan, Snjezana; Shen, Ronglai; Ang, Daphne C.; Johnson, Melissa L.; D'Angelo, Sandra P.; Paik, Paul K.; Brzostowski, Edyta B.; Riely, Gregory J.; Kris, Mark G.; Zakowski, Maureen F.; Ladanyi, Marc

doi:10.1158/1078-0432.ccr-11-3265

Cited by 639Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Research Studies

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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Dogan, Snjezana, Shen, Ronglai, Ang, Daphne C., Johnson, Melissa L., D'Angelo, Sandra P., Paik, Paul K., Brzostowski, Edyta B., Riely, Gregory J. +3 more·2012·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-11-3265PMC PMC3500422

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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. Clin Cancer Res; 18(22); 6169–77. ©2012 AACR.

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Among smokers, G12C is the commonest KRAS mutation (44%), followed by G12V (19%); G12D is the most frequent mutation in never-smokers (56%).
“While G12C is the commonest KRAS mutation among smokers (44%), followed by G12V (19%), G12D is the most frequent mutation in never-smokers (56%) [48].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [48]
KRAS G12C is the commonest KRAS mutation in NSCLC, seen in about 14% of all lung adenocarcinomas, followed by G12V.
“KRAS G12C is the commonest KRAS mutation in NSCLC, seen in about 14% of all lung adenocarcinomas, followed by G12V.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [48]
The basis of specific G12X mutation frequencies has remained unclear, except for the G12C transversion mutation associated with smoking in lung cancer.
“The basis of the specific G12X mutation frequencies has remained unclear, except for the G12C transversion mutation (c.34G>T) associated with smoking in lung cancer [6,7].”
From Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling (2018) · cites this paper as [7]
Cigarette smoking promotes G12C mutations exhibited regularly in the lung tissue.
“Finally, cigarette smoking promotes G12C mutations exhibited regularly in the lung tissue (Fig 1D and 1K) [7].”
From Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling (2018) · cites this paper as [7]

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Authors: Dogan, S., Shen, R., Ang, D. C., Johnson, M. L., D'Angelo, S. P., Paik, P. K., Brzostowski, E. B., Riely, G. J., Kris, M. G., Zakowski, M. F., & Ladanyi, M.
Affiliations: Authors' Affiliations: Departments of 1Pathology, 2Epidemiology and Biostatistics, 3Medicine, and 4Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Ladanyi, Marc
ORCID: Shen, Ronglai
Ang, Daphne C.
Johnson, Melissa L.
Paik, Paul K.
Riely, Gregory J.
Kris, Mark G.
Zakowski, Maureen F.
Ladanyi, Marc
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-11-14
Volume: 18
Issue: 22
Pages: 6169-6177
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-11-3265
PMC: PMC3500422
OpenAlex: W2166749501
Cited by: 639
References: 52
Citations by year: 2026: 39 · 2025: 45 · 2024: 55 · 2023: 49 · 2022: 68 · 2021: 87 · 2020: 61 · 2019: 46 · 2018: 33 · 2017: 21 · 2016: 38 · 2015: 41 · 2014: 35 · 2013: 19 · 2012: 2
FWCI: 25.03
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UL1TR000457)
National Cancer Institute (P01CA129243, NIH P01 CA129243)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: lung adenocarcinoma, EGFR mutation, KRAS mutation, smoking, sex differences, never smokers, pack-years, KRAS G12C, KRAS G12D, tobacco carcinogens, molecular epidemiology, passive smoking
MeSH terms: Adenocarcinoma of Lung, Adenocarcinoma, Adolescent, Adult, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Humans, Lung Neoplasms, Male, Middle Aged, Proto-Oncogene Proteins, Sex Factors, Smoking, Proto-Oncogene Proteins p21(ras), Molecular Epidemiology, ras Proteins, Genetic Predisposition to Disease, Mutation, Missense, Nomograms, Young Adult, Genetic Association Studies, ErbB Receptors

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