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Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 ( HER2 ) Tyrosine Kinase Mutations in Lung Adenocarcinomas
Open accessPublished version of a preprint
Abstract
Purpose: Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in U.S. patients. Experimental Design: Lung ADC samples (N = 1,478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2), and negative cases were then assessed for HER2 mutations (exons 19–20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, and AKT was conducted by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH. Results: We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared with insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12 bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2 mutations were more frequent among never-smokers (P < 0.0001) but there were no associations with sex, race, or stage. Conclusions: HER2 mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2. Clin Cancer Res; 18(18); 4910–8. ©2012 AACR.
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“Exon 20 of EGFR and HER2 contains two major regions, the α-C helix (residues 762–766 in EGFR and 770–774 in HER2) and the loop following the α-C helix (residues 767–774 in EGFR and 775–783 in HER2)16,19,20,27.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [19]
Experimental — accuracy not yet measuredIn the citing paper
“Together, EGFR and HER2 exon 20 mutations are found in approximately 4% of all patients with NSCLC19.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [19]
In the citing paper
“with the A775_G776insYVMA mutation accounting for most of the mutations seen in NSCLC (17–21).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [21]
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Metadata
- Authors
- Arcila, M. E., Chaft, J. E., Nafa, K., Roy-Chowdhuri, S., Lau, C., Zaidinski, M., Paik, P. K., Zakowski, M. F., Kris, M. G., & Ladanyi, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Department of Pathology, and 2Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
- National Institutes of Health (US)
- Corresponding author
- Arcila, Maria E.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-09-15
- Volume
- 18
- Issue
- 18
- Pages
- 4910-4918
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3865806
- OpenAlex
- W2107562400
- Cited by
- 505
- References
- 48
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 36 · 2023: 40 · 2022: 39 · 2021: 52 · 2020: 42 · 2019: 30 · 2018: 42 · 2017: 30 · 2016: 23 · 2015: 43 · 2014: 37 · 2013: 31 · 2012: 4
- FWCI
- 29.67
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (P01CA129243, T32CA009207, R25CA020449)
- 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
- HER2 mutation, lung adenocarcinoma, tyrosine kinase mutations, exon 20 insertion, never smokers, HER2 amplification, EGFR, KRAS, ALK rearrangement, molecular subtyping, clinicopathological features, molecular heterogeneity
- MeSH terms
- Adenocarcinoma, Adult, Aged, Aged, 80 and over, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Risk Factors, Prevalence, Survival Analysis, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Protein Interaction Domains and Motifs, DNA Copy Number Variations
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