1. Decreased Expression of the Chromatin Remodeler ATRX Associates with Melanoma Progression
- Author
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Emily Bernstein, Miriam B. Birge, Chen Chen, Zulekha A. Qadeer, David Valle-Garcia, Luis F. Duarte, Chiara Vardabasso, and Sara Harcharik
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Male ,X-linked Nuclear Protein ,Skin Neoplasms ,Dermatology ,Biochemistry ,Gene dosage ,Article ,Metastasis ,Cohort Studies ,medicine ,Humans ,Neoplasm Metastasis ,Melanoma ,Nevus ,Molecular Biology ,ATRX ,X chromosome ,biology ,DNA Helicases ,Nuclear Proteins ,Cell Biology ,DNA Methylation ,medicine.disease ,Chromatin ,Protein Structure, Tertiary ,3. Good health ,Gene Expression Regulation, Neoplastic ,Histone ,Mutation ,DNA methylation ,Cutaneous melanoma ,Disease Progression ,biology.protein ,Cancer research ,Female - Abstract
To the Editor ATRX is a member of the SWI/SNF family of chromatin remodelers, originally identified as mutated in patients with Alpha Thalassemia/Mental Retardation, X-linked syndrome. The protein product contains several highly conserved domains, including an ADD (ATRX-DNMT3-DNMT3L) domain that binds methylated histone H3 at lysine 9 and an ATPase domain responsible for its remodeling activities (Ratnakumar & Bernstein, 2013). Recently, whole genome sequencing studies identified ATRX mutations in multiple tumors, including those of neural crest cell origin: neuroblastoma, low-grade glioma and glioblastoma (Cheung et al., 2012; Heaphy et al., 2011a; Jiao et al., 2011; Kannan et al., 2012; Schwartzentruber et al., 2012). ATRX alterations encompass point mutations throughout the coding region as well as large N terminal deletions. While mechanistically unclear, ATRX mutations result in loss of protein as assessed by immunohistochemistry (IHC) and often correlate with alternative lengthening of telomeres (ALT) (Cheung et al., 2012; Heaphy et al., 2011a; Kannan et al., 2012; Schwartzentruber et al., 2012). To our knowledge, an investigation of ATRX in cutaneous melanoma is currently lacking. Our previous studies have demonstrated that decreased expression of histone variant macroH2A drives melanoma cell proliferation and metastasis (Kapoor et al., 2010), and that ATRX interacts with macroH2A to negatively regulate its association with chromatin (Ratnakumar et al., 2012). Taken together with recent reports of decreased ATRX protein in neural crest cell-derived tumors, we hypothesized that ATRX function might be compromised in melanoma. In order to test this hypothesis, we performed IHC on a panel of 23 benign nevi, 33 primary melanoma (≥1.0 mm deep) and 25 metastatic melanoma specimens that were formalin fixed paraffin embedded (FFPE) (Figure 1a, c). Slides were evaluated by two dermatopathologists in a blinded fashion using a scoring system based on number of positive nuclei and staining intensity (inter-rater correlation r=0.693, p more...
- Published
- 2014
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