Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience
Open accessAbstract
Introduction Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented.Methods Mutation testing in at least one of the eight genes (epidermal growth factor receptor [EGFR], KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, and PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing+/- peptide nucleic acid and/or sizing assays, along with anaplastic lymphoma kinase (ALK) and/or MET fluorescence in situ hybridization, were performed in six labs on 1007 patients from 14 institutions.Results In all, 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared with 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22%, 25%, 8.5%, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never-smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never-smoking status and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never-smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK, or MET.Conclusion Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations.
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- Authors
- Sholl, L. M., Aisner, D. L., Varella-Garcia, M., Berry, L. D., Dias-Santagata, D., Wistuba, I. I., Chen, H., Fujimoto, J., Kugler, K., Franklin, W. A., Iafrate, A. J., Ladanyi, M., Kris, M. G., Johnson, B. E., Bunn, P. A., Minna, J. D., & Kwiatkowski, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Colorado Anschutz (US)
- Vanderbilt University (US)
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Colorado Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Kwiatkowski, David J.
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 10
- Issue
- 5
- Pages
- 768-777
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC4410843
- OpenAlex
- W2009775937
- Cited by
- 430
- References
- 41
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 37 · 2023: 52 · 2022: 43 · 2021: 51 · 2020: 40 · 2019: 31 · 2018: 42 · 2017: 37 · 2016: 44 · 2015: 16
- FWCI
- 36.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (RC2CA148394, P50CA090578, P50CA070907, P50CA058187, P30CA008748, P01CA120964, P30CA016672, P30CA046934)
- 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 › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- lung adenocarcinoma, driver mutations, EGFR mutation, KRAS mutation, ALK rearrangement, ERBB2 mutations, PIK3CA mutation, MET amplification, clinicopathological correlation
- MeSH terms
- Anaplastic Lymphoma Kinase, Adenocarcinoma, Adrenal Gland Neoplasms, Bone Neoplasms, Cooperative Behavior, DNA Mutational Analysis, Female, Humans, Liver Neoplasms, Lung Neoplasms, Male, Mutation, Neoplasm Staging, Genes, ras, Sex Factors, Smoking, Gene Rearrangement, Genes, erbB-2, Genes, erbB-1, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Racial Groups, MAP Kinase Kinase 1, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Class I Phosphatidylinositol 3-Kinases
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