Use of clinical next‐generation sequencing to identify melanomas harboring SMARCB1 mutations. (24th March 2015)

• Record Type: Journal Article
• Authors: Stockman, David L.; Curry, Jonathan L.; Torres‐Cabala, Carlos A.; Watson, Ian R.; Siroy, Alan E.; Bassett, Roland L.; Zou, Lihua; Patel, Keyur P.; Luthra, Rajyalakshmi; Davies, Michael A.; Wargo, Jennifer A.; Routbort, Mark A.; Broaddus, Russell R.; Prieto, Victor G.; Lazar, Alexander J.; Tetzlaff, Michael T.
• Is Part Of: Journal of cutaneous pathology. Volume 42:Number 5(2015:May)
• Page Start: 308
• Page End: 317
• Publication Date: 2015-03-24
• Subjects: Skin -- Diseases -- Periodicals; Dermatology -- Periodicals; 616
• DOI: 10.1111/cup.12481
• Languages: English
• ISSNs: 0303-6987

Abstract

<abstract abstract-type="main" id="cup12481-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cup12481-sec-0001" sec-type="section"> <title>Background</title> <p id="cup12481-para-0001"> <italic>SMARCB1</italic> (<italic>INI1</italic>/<italic>BAF47</italic>/<italic>SNF5</italic>) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney.</p> </sec> <sec id="cup12481-sec-0002" sec-type="section"> <title>Methods</title> <p id="cup12481-para-0002">A 46‐gene or 50‐gene next‐generation sequencing AmpliSeq Cancer Panel (Life Technologies; San Francisco, CA, USA) was applied to ∼1400 primary or metastatic melanoma tissues.</p> </sec> <sec id="cup12481-sec-0003" sec-type="section"> <title>Results</title> <p id="cup12481-para-0003">We identified eight cases of melanoma harboring mutations in <italic>SMARCB1</italic>. Immunohistochemistry demonstrated preservation of SMARCB1 protein expression in all cases. <italic>SMARCB1</italic> mutations occurred together with <italic>TP53</italic> mutations in five of the eight cases, suggesting a functional relationship between these tumor suppressors in melanoma.</p> </sec> <sec id="cup12481-sec-0004" sec-type="section"> <title>Conclusions</title> <p id="cup12481-para-0004">Because single‐base substitutions in <italic>SMARCB1</italic> occur in a small subset of melanomas and do not affect SMARCB1 protein expression, such mutations would only be discovered by sequencing approaches. Our findings highlight the potential for next‐generation sequencing platforms to identify mutations unexpected for melanoma that may contribute to its oncogenic potential. Though rare, the identification of <italic>SMARCB1</italic> mutations adds to the growing literature regarding the role of epigenetic control mechanisms in melanoma progression and therapeutic resistance and provide a rationale for strategies targeting such alterations (via chromatin remodeling agents) in clinical trials.</p> </sec> </abstract>