CDK4 gene copy number increase and concurrent genetic changes in acral melanoma of a Chinese cohort

Abstract

Acral melanoma (AM) is the most common subtype of melanoma in Asian population. Abnormalities in the p16-cyclin D1-CDK4 signaling pathway play a crucial role in the development and progression of acral melanoma. However, the alterations of CDK4 gene copy number in acral melanoma are under reported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with acral melanoma, in aim of exploring CDK4 gene alterations and its significance in acral melanoma. We examined copy number alterations of CDK4 with fluorescence in situ hybridization (FISH) in 31 acral melanomas. Six patients with CDK4 high-level copy number increase were examined by next generation sequencing (NGS) to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with 6 (6/31, 19.4%) low-level copy number increase and 6 (6/31, 19.4%) high-level copy number increase. 5 of 6 CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while 1 case was not. 2 of 6 CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while 4 cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In 6 CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation, and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in acral melanoma cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of acral melanoma. Some CDK4 copy number increase are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in acral melanoma. CDK4 appears to be a promising target for acral melanoma treatment and is expected to be combined with other targeted therapies.