Aberrations of KIT, BRAF, NRAS, and PDGFRA in Chinese melanoma patients and their significance: Large, scale analysis of 644 patients.

Abstract

8568 Background: Mutations in KIT, BRAF, NRAS and PDGFRA are common in melanoma, which have not been extensively studied in Asia. We examined these aberrations and correlated the aberrations to the clinical features and survival in Asian melanoma patients. Methods: This study involved samples from 644 melanoma patients in Peking University Cancer Hospital. Clinical data were collected. Tissue samples were analyzed for mutations in KIT (exons 9,11,13,17,18), BRAF (exons 11,15), NRAS (exons1,2) and PDGFRA (exons 12,14,18) genes by PCR amplification and Sanger sequencing. The copy numbers of KIT gene were analyzed by quantitative PCR. Results: The incidence of somatic mutations within the KIT, BRAF, NRAS and PDGFRA genes was 10.1% (58/573), 25.9% (121/468), 7.2% (33/459) and 4.8% (17/352), respectively. The incidence of increased KIT copy number was 7.6% (39/516). The highest KIT mutation frequency is within the CSD subgroup (27.3%, 9/33). Increased KIT gene copy number was comparatively more frequent in acral (8.0%, 14/176) and mucosal (11.5%, 17/148) melanomas than in CSD (3.2%, 1/31) and Non-CSD (1.9%, 2/104) melanomas. Surprisingly, BRAF mutations were detected in 17.9% (28/156) of acral melanomas and 12.5% (16/128) of mucosal melanomas. The most frequent mutation in BRAF was V600E (87.3%). The median follow-up period was 24 (3~229) months (n=473). No statistical differences were found for thickness and ulceration rates between melanomas with or without these mutations (P=0.6). The median survival for patients with KIT mutations (30 months) and BRAF (33m) were significantly shorter than for patients with WT tumors (53m; P=0.01, P=0.005 respectively). Overall survivals were similar in groups with or without NRAS and PDGFRA mutations. Conclusions: KIT and BRAF are important oncogenes in Asian melanomas. Mutations in the BRAF gene were more common than KIT mutations. For the first time, our study suggests that genetic KIT and BRAF aberration is an adverse prognostic factor for melanoma. These results suggest that the KIT inhibitor as well as BRAF V600E inhibitor might play their roles in Asian melanoma patients. Supported by the National Natural Science Foundation of China30973483.