Article Abstract

cMET-N375S germline mutation is associated with poor prognosis of melanoma in Chinese patients

Authors: Tian-Xiao Xu, Si-Fan Yu, Meng Ma, Jie Dai, Zhi-Hong Chi, Lu Si, Xi-Nan Sheng, Chuan-Liang Cui, Yan Kong, Jun Guo


Background: cMET has been known to play an essential role in malignant melanoma tumor progression. Recent studies have shown that a germline missense variant in exon 2 of the cMET, N375S (rs33917957 A>G) occurred at a much higher frequency in East Asian patients with lung cancer. However, the status of this mutation in melanoma is unclear. In this study, we examined the mutation frequency of cMET-N375S in 181 melanoma samples and analyzed its clinicopathological significance.
Methods: Tissue samples (n=181) were analyzed for cMET-N375S, BRAF, NRAS, and CKIT mutation in genomic DNA by polymerase chain reaction amplification and Sanger sequencing. The levels of p-cMET protein were determined by immunohistochemistry. Clinical data of patients were also collected.
Results: We identified a highly frequent variant (N375S) of cMET in 13.26% (24/181) of the patients with melanoma. This mutation was relatively more frequent in acral (22.8%) and mucosal (12.7%) melanomas (the two most common melanoma subtypes in Asian, but not in Caucasians) than in non-chronic sun induced damage (non-CSD; 5.9%) and CSD (8.3%) melanomas. Among the 24 cases with cMET-N375S mutations, six cases were found to harbor the BRAF mutation, four cases harbored NRAS mutations, and two cases harbored CKIT mutations. And there was no correlation between this mutation and p-cMET levels. Kaplan- Meier analysis showed significant differences in overall survival (OS) and disease-free survival (DFS) between the N375S mutation group and non-N375S mutation group (P=0.039; P=0.030). The Cox proportional hazards model revealed that cMET-N375S mutation was an independent adverse prognostic factor for OS [P=0.003, hazard ratio (HR) =3.577].
Conclusions: Our findings suggested that the cMET-N375S mutation was an adverse prognostic factor for melanoma in a Chinese cohort.