Genetic and Epigenetic Analysis of erbB Signaling Pathway Genes in Lung Cancer

Background: Prognosis for patients with non-small cell lung cancer (NSCLC) is poor. The potential value of modulating epidermal growth factor receptor (EGFR) for treatment is reflected by the recent approval of specific drugs that inhibit its activity. Mutations in EGFR were reported in lung cancer and generated interest, once they enable the identification of lung cancers likely to respond to various targeted small molecules. Methods: We tested three key genetic and epigenetic alterations (EGFR, RASSF1A, and BRAF) of this pathway on a series of primary NSCLC (total 111; adenocarcinoma 49, squamous cell carcinoma [SCC] 48, and others 14). The mutational status of KRAS (and p53) was known for these samples. The purpose of this study was to define the pattern of erbB pathway alterations in NSCLC and to test for associations with clinical parameters. Results: Five EGFR mutations were identified: three in adenocarcinoma (6%), one in SCC (2%), and one with poorly differentiated NSCLC, classified as “others” (7%). EGFR mutations included three in-frame deletions in exon 19 and two point mutations in exon 21. Promoter methylation of RASSF1A was detected in 25 of 45 adenocarcinomas and 18 of 46 SCC. Mutations of EGFR, BRAF, and KRAS in adenocarcinoma were mutually exclusive and inversely correlated with RASSF1A methylation (&rgr; = −0.394; p = 0.007). Discussion: Overall, genetic and/or epigenetic alterations of erbB pathway genes were detected in 80% (39/49) of adenocarcinomas. Approximately half of primary adenocarcinoma harbor molecular alterations of the erbB pathway. Careful characterization of these alterations and response to anti-EGFR therapies is warranted to determine better and accurate determinants of clinical response.