Genetic evolution of EGFR and the clonal origin of adenocarcinomas exhibiting various degrees of bronchioloalveolar carcinoma

Abstract

e22050 Background: EGFR mutations may accumulate during multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. Moreover, intrapulmonary emersions are the predominant sites of BAC progression in the absence of other distant metastases. In cases of emerging bilateral lung lesions during the follow-up to complete resection, the issue of how to differentiate between lesions originating from multifocal BACs or distant metastases/local recurrence is an important and unresolved issue. This study was performed to determine whether sequential adenocarcinoma with BAC features emerges in the lung field arises from a single clone or multiple clones in the same individual. Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained on detection of novel lesions in the lung field. Genomic DNA was extracted from the specimens, and the presence of activating mutations in EGFR was analyzed by direct sequencing. Our pathological findings, sequential imaging, and EGFR sequence data were compared to monitor evidence of cancer evolution. Results: Based on an analysis of EGFR in tumor specimens from 428 lung cancer patients, fifteen cases of sequential BAC-related adenocarcinoma obtained by thoracotomy were identified. Together with alterations in BAC/adenocarcinoma components, the EGFR-TKI untreated series with at least one episode of EGFR-activating mutations represented three typical models: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, and a switch from wild-type to mutant EGFR, which might exhibit uncertain circumstances of cancer progression. Conclusions: Genetic analysis in conjunction with pathological and radiological diagnoses can be used to explore the origin of multifocal BAC. The single clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of secondary primary carcinoma. When additional lesions emerge after radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation. No significant financial relationships to disclose.