Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer

Abstract

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714-23) Lung cancer is a difficult disease to treat and is the most commonly diagnosed form of cancer, and its ravages on human health is underscored by the fact that there are over 213,000 new cases every year in the United States alone. Despite significant advances in treatments over the past two decades, only 15% of lung cancer patients survive for 5 years or longer (1). However, one of the most interesting and intriguing facts that has emerged from recent ethnic studies is that African Americans

Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry

“…We also present the results of a retrospective analysis of African-American patients with NSCLC seen at our institution, showing a significantly higher prevalence of EGFR mutations in this patient population than previously reported in the literature. (Yang et al, 2005;Krishnaswamy et al, 2009;Leidner et al, 2009). Additionally, we present data on the molecular and functional characterization of three exon 20 mutations found in African-American patients with NSCLC.…”

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

“…MET alterations included two different missense mutations in the JM domain (R988C found in NCI-H69 and H249 cell lines; and T1010I in SCLC tumor sample). Also, a semaphorin domain missense mutation (E168D in SCLC tumor sample), two-base-pair insertional mutations [IVS13- (52)(53)insCT in SCLC tumor samples] within the pre-JM intron 13, as well as an alternative transcript involving exon 10 (H128 cell line), were identified (42). The two reported JM mutations affected cell proliferation, resulting in small but significant growth factor independence in the IL3-dependent BaF3 cell line, and were found to regulate cell morphology and adhesion, and enhanced tumorigenicity when introduced into an SCLC cell line (42).…”

“…In one patient with largecell carcinoma who was treated for over 5 months, there was a partial response comprising a 53% reduction in tumor, and in the other patient, who had squamous NSCLC that had failed prior therapies and was treated for 13 months, there was a partial response comprising a 61% reduction in tumor (43). MET mutations in the semaphorin domain have been shown to affect ligand binding: MET-N375S, the most frequent mutation of MET, most common among male smokers and squamous cell carcinoma, confers resistance to MET inhibition based on HGF binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies (53).…”

Establishment and application of a multiplex genetic mutation-detection method of lung cancer based on MassARRAY platform

“…So a robust genotyping platform which can carry-on daily routine testing is need. Other multiplex genetic mutation-detection methods have been reported, such as Cancer Personalized Profiling by deep sequencing and SNaPShot 7,15 . Molecular characterization via MALDI-TOF on MassARRAY platform, which is characterized by high throughput, high sensitivity, and a simple operation, can be implemented by combining single-base extension and mass spectrometry technology.…”