Data from <i>SF3B1</i> Mutations Are Associated with Alternative Splicing in Uveal Melanoma

Abstract

<div>Abstract<p>Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified <i>SF3B1</i> mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. <i>SF3B1</i> mutations were associated with good prognosis and were rarely coincident with <i>BAP1</i> mutations. <i>SF3B1</i> encodes a component of the spliceosome, and RNA sequencing revealed that <i>SF3B1</i> mutations were associated with differential alternative splicing of protein coding genes, including <i>ABCC5</i> and <i>UQCC</i>, and of the long noncoding RNA <i>CRNDE</i>.</p><p><b>Significance:</b> Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that <i>SF3B1</i> is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing. <i>Cancer Discov; 3(10); 1122–9. ©2013 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1083</p></div>