Impact of MET amplification on gastric cancer: Possible roles as a novel prognostic marker and a potential therapeutic target

Abstract

Abstract.Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. With the aim of establishing personalized medicine for treatment of solid tumors, we focused on MET amplification in gastric cancer patients, given the extreme sensitivity to c-Met inhibitor in MET amplified gastric cancer cell lines. We tested MET amplification and activation of c-Met in various gastric cancer cell lines and tissue samples from 482 gastric cancer patients who underwent curative surgery. Gastric cancer cell lines with MET amplification by quantitative real-time PCR (qPCR) and FISH predicted sensitivity to PHA-665,752, a selective c-Met kinase inhibitor. Of the 472 patients who had DNA sample available for qPCR analysis, 100 patients (21.2%) had a MET copy number greater than 4.0 copies and demonstrated poorer survival following curative surgery with statistical significance (5-year OS; 50.0 vs. 59.1%; MET amplification (+) vs. MET amplification (-); P=0.0134). These results suggest that the increased MET copy number measured by qPCR plays an important role in determining prognosis in gastric cancer patients. However, the predictive role of MET amplification for treatment response should be further explored in upcoming clinical trials. IntroductionGastric cancer is the leading cause of cancer death worldwide with the incidence of 18.9/100,000 per year (1). The incidence of gastric cancer was estimated to be 934,000 cases, with 56% of the new cases occurring in East Asia (2). Gastric cancer accounts for 20.8% of all cancers in Korea according to the Central Tumor Registry data for 2002 (3). Although overall survival of gastric cancer has been enhanced owing to the application of national fiberoptic esophagogastroduodenoscopy (EGD) screening program in adults aged over 40 years in Korea, a large proportion of patients are still diagnosed at metastatic stage. The median survival time following cytotoxic chemotherapy is still less than 1 year and thus, metastatic gastric cancer remains a therapeutic challenge for medical oncologists. The role of molecularly targeted therapy has not been adequately explored in gastric cancer when compared to other common solid tumors such as non-small cell lung cancer, breast or colorectal cancer.The MET oncogene encodes the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF) and controls genetic programs leading to cell growth, invasion and protection from apoptosis (4). Although the definitive role of MET oncogene is yet to be determined in carcinogenesis of gastric cancer, overexpression and amplification of c-Met has been demonstrated in gastric cancer cell lines (5-9). In addition, approximately 10-20% of gastric cancer tissues and up to 40% of the scirrhous histological subtype were shown to harbor increased MET gene copy numbers (6,10,11). Importantly, PHA-665,752, a selective c-Met kinase inhibitor showed significant reduction of established tumor mass in mouse xenografts with GTL...

Clinical significance of MET in gastric cancer

“…Gene amplification has been found to be significantly related to distant metastasis and tumor stage [12,39] . On copy number assay using reverse transcription polymerase chain reaction (RT-PCR), MET gene amplification was observed in 1.5% to 30% of tumors, although the definition of MET amplification somewhat differed among studies [15,18,[40][41][42] . In a study using single nucleotide polymorphism array, MET amplification was detected in 3% to 4% of patients [43,44] .…”

“…Wang et al [43] reported that MET amplification was found in 7% (3 of 41) of intestinal type cancers, but not in other types. In many studies using FISH or RT-PCR, patients with MET-amplified tumors had significantly poorer survival than those with non-amplified tumors [12,15,18,32,39,41,42] . Only a Japanese study, with the lowest incidence of gene amplification, reported no relation of MET amplification to survival or any clinicopathological characteristic [40] .…”

“…Similar to other RTKs, MET plays key roles in tumor survival, growth, angiogenesis, and metastasis. The aberrant signaling of MET by overexpression or gene amplification has been detected and correlated with tumor progression or patients' survival in GC [12][13][14][15] . Alternative activation of the MET pathway is considered an important mechanism causing resistance to treatments targeting HER family members [16,17] .…”

The prognostic impact of EGFR, ErbB2 and MET gene amplification in human gastric carcinomas as measured by quantitative Real-Time PCR

“…Oncogenic activation of MET promotes cell proliferation, survival, migration, angiogenesis and apoptosis inhibition (Birchmeier et al 2003). Recently, several studies have shown the MET gene amplification is one of the causes of MET overexpression in GC; however, the frequency of MET amplification is various among previous studies (Lee et al 2011(Lee et al , 2012Huang and Chuang 2013;Kawakami et al 2013).…”

Gastric Cancer Pathology and Underlying Molecular Mechanisms

“…Overexpression of MET has been related to tumor stage and clinical outcome [67]. With the advent of MET inhibitors, the interest in this molecule had a revival, and a very recent large study conducted in Korea demonstrated that MET was amplified in 21% of GC and related to poor patient survival [68]. …”