Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

Shigematsu, H.; Lin, L.; Takahashi, T.; Nomura, M.; Suzuki, M.; Wistuba, I. I.; Fong, K. M.; Lee, H.; Toyooka, S.; Shimizu, N.; Fujisawa, T.; Feng, Z.; Roth, J. A.; Herz, J.; Minna, J. D.; Gazdar, A. F.

doi:10.1093/jnci/dji055

Cited by 2,377Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H. +8 more·2005·JNCI Journal of the National Cancer Institute

DOI 10.1093/jnci/dji055

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Abstract

BACKGROUND: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. METHODS: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. RESULTS: We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. CONCLUSIONS: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.

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The prevalence of EGFR mutations varies by ethnicity, from 5-10% in white patients to 60-70% in never-smoking Asian patients with adenocarcinoma.
“For example, the prevalence of EGFR mutations ranges from between 5% and 10% in whites to between 60% and 70% in neversmoking Asian patients with adenocarcinoma”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [3]

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“Non-small cell lung cancer (NSCLC), triggered by the activation of epidermal growth factor receptor (EGFR) mutations, accounts for approximately 10% of all NSCLC cases (1).”
Background

Assessing the significance of KRAS G12C mutation: Clinicopathologic features, treatments, and survival outcomes in a real-world KRAS mutant non-small cell lung cancer cohort.
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Authors: Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., Fujisawa, T., Feng, Z., Roth, J. A., Herz, J., Minna, J. D., & Gazdar, A. F.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Shigematsu, H.
ORCID: Nomura, M.
Wistuba, I. I.
Fong, K. M.
Lee, H.
Toyooka, S.
Shimizu, N.
Feng, Z.
Roth, J. A.
Herz, J.
Minna, J. D.
Gazdar, A. F.
Venue: JNCI Journal of the National Cancer Institute
Publisher: Oxford University Press (OUP)
Published: 2005-03-01
Volume: 97
Issue: 5
Pages: 339-346
ISSN: 0027-8874 (ISSN-L)
1460-2105
DOI: 10.1093/jnci/dji055
OpenAlex: W2143859186
Cited by: 2,377
References: 44
Citations by year: 2026: 41 · 2025: 53 · 2024: 63 · 2023: 69 · 2022: 104 · 2021: 77 · 2020: 96 · 2019: 102 · 2018: 103 · 2017: 120 · 2016: 123 · 2015: 132 · 2014: 127 · 2013: 149 · 2012: 134
FWCI: 134.07
Type: journal article
Language: en
Open access: closed
Locations: JNCI Journal of the National Cancer Institute (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart, Lung, and Blood Institute (R37HL063762)
National Cancer Institute (P50CA070907, 5U01 CA 8497102)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: EGFR mutation, epidermal growth factor receptor, non-small cell lung cancer, tyrosine kinase domain, KRAS mutation, lung cancer pathogenesis, never smokers, adenocarcinoma, exon 19 deletion, exon 20 insertion, sex differences, East Asian ethnicity, EGFR tyrosine kinase inhibitors, molecular subtyping
MeSH terms: Adenocarcinoma, Australia, Carcinoma, Non-Small-Cell Lung, DNA, Viral, Female, Humans, Japan, Lung Neoplasms, Male, Mutation, Neoplasm Staging, Protein-Tyrosine Kinases, Genes, ras, Taiwan, United States, Mutagenesis, Insertional, Sequence Analysis, DNA, Carcinoma, Neuroendocrine, Genes, erbB-1, Mutation, Missense, Gene Duplication, Papillomaviridae, White People, Asian People

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Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

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