In this study, we investigated the prognostic role of the MET CNAs in surgically resected PI-DLBL and found that tumors with MET CN gain greater than 3 copies were associated with an unfavorable prognosis and also with perforation at disease presentation. Normal or lower level MET CN gain also denoted a trend toward poor prognosis, although the statistical significance was low. We speculate that the clinical impact of MET CN on prognosis might be amplification dosage dependent. Furthermore, we re-confirmed our previous findings that tumor perforation was a poor prognostic factor in PI-DLBL and that the relative frequency of GCB phenotype was low in PI-DLBL, although the latter was not significantly related to prognosis .
HGF/MET pathway could be activated in both benign and malignant B-cells. Amplification of the MET gene would result in MET protein over-expression and constitutive kinase activation . MET CNAs have been investigated in solid cancer such as gastric carcinoma and NSCLC [8–10]. Depending on the methods for assessing MET CNAs, MET amplification has been identified in 4-21% of gastric carcinomas [23, 24]. An increase of MET CN was associated with higher tumor stage at presentation and poorer survival in patients with gastric cancer [10, 25]. For a subset of lung cancers with acquired resistance to epidermal growth factor receptor-targeting therapy, MET amplification is one of the most frequently involved mechanisms . In NSCLC, MET gene has been shown to be amplified in 21-24% of tumors and the impact of MET CN on prognosis is histological subtype dependent: MET amplification with a poorer prognosis in patients with adenocarcinoma but not in those with squamous cell carcinoma [9, 27].
Among the various entities of non-Hodgkin lymphomas, MET is frequently over-expressed in DLBL [14, 15, 17]. Over-expression of HGF/MET signaling activates downstream molecules that control proliferation, adhesion and apoptosis. In the literature, however, the prognostic significance of MET over-expression in DLBL is controversial. High serum HGF levels and overactive HGF/MET pathway in DLBL patients have been reported to be linked with unfavorable outcome in several studies [14, 28, 29]. On the other hand, Uddin et al. showed a better overall survival at 5 years in DLBL patients with MET over-expression than those with low MET expression level (76.2% vs. 57.5%; P = 0.0025) . A study from the Middle East also showed that MET over-expression carried a better prognosis in DLBL patients . So far MET gene CN has not been investigated in malignant lymphoma yet. To the best of our knowledge, our study is the first report describing the prognostic significance of MET CNAs in patients with PI-DLBL. Our results suggested that higher MET CN, possibly leading to MET over-expression, might be a poor prognostic indicator for PI-DLBL.
High serum HGF levels have been found in patients with DLBL and MM, and they were associated with an unfavorable prognosis [14, 30–32]. Furthermore, tumor cells could up-regulate HGF production, through paracrine and/or autocrine mechanisms, by the surrounding stromal cells or cancer cells themselves [7, 33]. With the recent development of clinical-grade agents targeting the HGF/MET pathway, inhibition of this pathway is currently considered a rational and promising strategy for the treatment of patients with B-cell lymphoma and MM [13, 34]. Among these agents, Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small-molecule inhibitor of c-MET and anaplastic lymphoma kinase, and is considered a very potential agent for treatment of cancers dependent on these oncogenic kinases for growth and survival [35, 36]. Our results of high MET CN gain in PI-DLBL patients with poor prognosis suggested that blocking HGF/MET pathway might be a promising adjuvant therapeutic option.