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Genomic Evolution in a Patient With Lung Adenocarcinoma With a Germline EGFR T790M Mutation
Netta Mäkinen1,2, Meng Zhou1,2, Meredith Bemus3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Introduction:
A subset of lung adenocarcinomas (ADs) has been found to have somatic activating mutations in the tyrosine kinase domain of the EGFR gene, associated with response to EGFR tyrosine kinase inhibitor therapy. Rare germline mutations within this domain, including EGFR T790M, have been associated with genetic susceptibility to lung ADs. Using high-throughput sequencing, we elucidate the genomic evolution in tissues from a patient with lung AD carrying a germline EGFR T790M mutation.
Methods:
We performed microdissection, targeted panel, and whole-exome sequencing to molecularly characterize multiple foci of atypical adenomatous hyperplasia (AAH), in situ and invasive components of AD, normal lung tissue, and whole blood from the patient. Normal lung tissue was analyzed for potential acquired somatic genome alterations ("field effect").
Results:
All lesions harbored a secondary somatic EGFR mutation, either L858R or L861Q, in addition to the germline T790M mutation. Clear overlap was observed between the somatic profiles of in situ and invasive AD components, confirming clonal relatedness. AAH lesions shared few to no somatic alterations with the AD, suggesting clonal independence. No robust evidence of field effect was identified in the normal lung tissue.
Conclusions:
Somatic EGFR mutations are early events in the pathogenesis of lung ADs arising in the context of germline EGFR T790M. Synchronous AAH lesions seem to be independent. Stepwise genomic evolution is observed in association with invasiveness of the neoplastic cell population.
Insights
Somatic EGFR mutations are early events in lung adenocarcinoma (AD) developing in patients with a germline EGFR T790M mutation. Genomic evolution correlates with tumor invasiveness, with distinct AAH lesions appearing independent.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Activating mutations in the Epidermal Growth Factor Receptor (EGFR) gene are common in lung adenocarcinomas (ADs) and predict response to tyrosine kinase inhibitor (TKI) therapy.
- Rare germline mutations in the EGFR tyrosine kinase domain, such as T790M, are linked to inherited susceptibility to lung AD.
- Understanding the genomic evolution of lung AD in individuals with germline EGFR mutations is crucial for elucidating disease pathogenesis.
Purpose of the Study:
- To investigate the genomic evolution of lung adenocarcinoma in a patient with a germline EGFR T790M mutation.
- To characterize the molecular profiles of various neoplastic and normal tissues from the patient.
- To determine the role of somatic EGFR mutations in the early stages of lung AD development.
Main Methods:
- Microdissection and targeted panel sequencing of atypical adenomatous hyperplasia (AAH), in situ and invasive AD components, and normal lung tissue.
- Whole-exome sequencing of tumor and germline DNA (whole blood).
- Analysis of normal lung tissue for potential acquired somatic genome alterations (field effect).
Main Results:
- All lung lesions, including in situ and invasive AD, harbored a secondary somatic EGFR mutation (L858R or L861Q) alongside the germline T790M mutation.
- Somatic mutation profiles of in situ and invasive AD components showed significant overlap, indicating clonal relatedness.
- AAH lesions exhibited limited shared somatic alterations with AD, suggesting independent clonal origins. No significant field effect was detected in normal lung tissue.
Conclusions:
- Somatic EGFR mutations appear to be early events in the development of lung AD in the context of a germline EGFR T790M mutation.
- Independent clonal evolution characterizes AAH lesions, while stepwise genomic progression is observed with increasing invasiveness of AD.
- Germline EGFR T790M mutations may predispose individuals to lung AD through early somatic alterations.
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