Loss of SNF5 Expression Correlates with Poor Patient Survival in Melanoma

Abstract

Purpose: Aberrant expression of SWI/SNF chromatin remodeling complex is involved in cancer development. The tumor suppressor SNF5, the core subunit of SWI/SNF complex, has been shown to regulate cell differentiation, cell cycle control, and apoptosis. To investigate the role of SNF5 in the development of melanoma, we examined the expression of SNF5 in melanocytic lesions at different stages and analyzed the correlation between SNF5 expression and clinicopathologic variables and patient survival. Experimental Design: Using tissue microarry and immunohistochemistry, we evaluated SNF5 staining in 51 dysplastic nevi, 88 primary melanomas, and 48 metastatic melanomas. We studied chemosensitivity of melanoma cells with reduced SNF5 expression by siRNA using cell survival and apoptosis assays. Results: SNF5 expression was reduced in metastatic melanoma compared with dysplastic nevi (P = 0.005), in advanced primary melanoma (Clark's level V) compared with low risk Clark's level II melanoma (P = 0.019), and in melanoma at sun-exposed sites compared with sun-protected sites (P = 0.044). Furthermore, we showed a strong correlation between negative SNF5 expression and a worse 5-year survival in melanoma patients (P = 0.016). Multivariate Cox regression analysis revealed that negative SNF5 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.031). Finally, we showed that knockdown of SNF5 in melanoma cell lines resulted in significant chemoresistance. Conclusions: Our data indicate that SNF5 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target. (Clin Cancer Res 2009;15(20):6404-11) Human cutaneous malignant melanoma is a life-threatening skin cancer, for its ability to metastasize rapidly and its resistance to conventional radiotherapy and chemotherapy (1, 2). Although melanoma accounts for only 4% of skin cancers, it is responsible for 80% of deaths from skin cancer (3). Furthermore, although melanoma is curable through early diagnosis and surgical excision (4), up to 20% of patients will develop metastatic tumor due to its highly invasive and metastatic properties (5). Consequently, metastatic melanoma patients have a poor prognosis, with median survival of only 6 to 10 months and <5% of the patients surviving >5 years (4, 6, 7). SWI/SNF ATP-dependent chromatin-remodeling complex is a 2-Mda multsubunit complex first identified in yeast and highly conserved among eukaryotes (8). SWI/SNF complexes play essential roles in transcriptional regulation, contribute to the control of cellular processes, such as proliferation and differentiation, and also are involved in DNA repair by altering the accessibility of UV-damaged DNA-binding proteins to DNA lesions (9-13). SNF5, also known as INI1/BAF47/SMARCB1, is the core subunit of mammalian SWI/SNF complex. Many genetic evidences have defined SNF5 as a tumor suppressor gene in humans and mice. In mice, homozygous deletion of SNF5 is embryonic lethal, and heterozy...

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

“…40 In accordance with its tumor suppressor function immunohistochemical loss of SMARCB1 expression has been reported as an independent prognostic factor of reduced survival in malignant melanoma. 41 Lastly, the PTPN11 mutation in case 18 is an unequivocal, confirmed somatic mutation (SIFT score 0.04) previously observed in a melanoma 42 and in acute lymphoblastic leukemia. 43 Of note the mutation panel employed in our study also included hotspot mutation analysis for GNAQ and GNA11 two G-protein subunits leading to constitutive activation of the ERK signalling cascade.…”

Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

“…In the present analysis, the most certain (lowest P-value) observed effects on outcome were exhibited by the MPDs: p16/INK4a, together with survivin and p53 (18); b-catenin combined with fibronectin, activating transcription factor (ATF)2, p16/INK4a, and p21/ WAF1 (21); and RGS1 and SPP1/osteopontin with NCOA3 (22 (24). Tests involving a-catenin showed no significance in a univariate analysis but significant association with outcome in a multivariate setting (21).…”

Roles of SWI/SNF Complex Genes in Breast Cancer

“…Furthermore, loss of Ini1 was redundant with loss of Rb function in the formation of pituitary tumors in Rb heterozygous mice and gave rise to the formation of large, atypical Rb(+/-) tumor cells lacking adrenocorticotropic hormone expression, confirming in vivo the relationship between Rb and Ini1 in tumor suppression [74]. Mutations and alterations of SNF5 were also reported in familial schwannomatosis and other cancer types [75][76][77][78][79][80][81][82][83][84]. Germ line mutations of SNF5 were detected in brain tumors and rhabdoid tumors, suggesting its link with familial cancers [85][86][87][88].…”