Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor

• Published in: Journal of thoracic oncology Vol. 10; no. 9; pp. 1292 - 1300
• Main Authors: Yeung, Sai F., Tong, Joanna H.M., Law, Peggy P.W., Chung, Lau Y., Lung, Raymond W.M., Tong, Carol Y.K., Chow, Chit, Chan, Anthony W.H., Wan, Innes Y.P., Mok, Tony S.K., To, Ka F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015; Copyright by the International Association for the Study of Lung Cancer
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; ALK; Biomarker; BRAF; Cohort Studies; Driver mutations; East Asian lung cancer; EGFR; Female; Genetic marker; HER2; Humans; In Situ Hybridization, Fluorescence - methods; KRAS; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; MET; MET amplification; Middle Aged; Molecular classification lung cancer; NRAS; Oncogenic driver mutation; Prognosis; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Retrospective Studies; RIT1; ROS1; Targeted therapy; TTF-1 lung adenocarcinoma; ALK; Molecular classification lung cancer; Biomarker; Genetic marker; Targeted therapy; Lung cancer; Oncogenic driver mutation; TTF-1 lung adenocarcinoma; BRAF; EGFR; RIT1; NRAS; Driver mutations; KRAS; MET amplification; East Asian lung cancer; HER2; MET; ROS1
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0000000000000620

Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.