Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: Mutations are mainly present in adenocarcinomas with bronchioloalveolar features

Abstract

Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCRsingle strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p 5 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors. ' 2006 Wiley-Liss, Inc.Key words: HER2; EGFR; genetic mutations; lung cancer; bronchioloalveolar carcinoma Lung cancer is the main cause of cancer-related death in developed countries, with NSCLC accounting for about 80% of cases.

Pulmonary Large Cell Carcinoma Lacking Squamous Differentiation Is Clinicopathologically Indistinguishable From Solid-Subtype Adenocarcinoma

“…This frequency is higher than the 25% reported in lung ADC from unselected patients, 29 likely reflecting the high numbers of smokers in these cohorts. [30][31][32][33][34] KRAS transversion mutations in particular have been linked to smoking history in prior studies 30,35,36 ; among the KRAS mutations detected in our study, approximately 90% were transversions, confirming this association.…”

Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond

“…It is now clear that mutations in EGFR, KRAS, BRAF and ERBB2 are essentially mutually exclusive in lung adenocarcinoma 19,[45][46][47][48][49] (Figure 2). This reflects the fact that they represent alternative ways of oncogenically activating some of the same downstream pathways, including the PI3K-AKT pathway and the MAPK pathway (Figure 1).…”

“…ERBB2 mutations (in-frame insertions in exon 20; not amplification) occur in about 1-2% of adenocarcinomas and interestingly these, like EGFR-mutant tumors, often show BAC features, and occur preferentially in never smokers and women. 46,47,50 The presence of a KRAS mutation is both an adverse prognostic factor 14 and a predictor of failure to benefit from EGFR TKI therapy. [51][52][53] Indeed, in one study this went beyond a simple lack of response in that tumors with KRAS mutations did significantly worse when an EGFR TKI was added to their standard chemotherapy.…”

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…HER‐2 kinase domain mutations can be categorized as: missense point mutations, small in‐frame insertions or duplications which almost occurring in exon 20 and in frame deletions. Among these mutations, the in‐frame insertions or duplications in exon 20 are the most frequently encountered types of mutations 22, 30, 31, 32. In addition, we also take the HER‐2 splice variants into account, including p95HER‐2 and Δ16HER‐2.…”