Exome capture identifies recurrent somatic mutations in EIF1AX and SF3B1 anti-correlated in uveal melanoma with disomy 3

Gene expression profiles and chromosome 3 copy number divide uveal melanoma (UM) into two distinct classes correlating with patients' prognosis. Using exome sequencing we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in UM with disomy 3 (D3), which rarely metastasize. Targeted re-sequencing showed that 24 (77%) of 31 tumors with D3 had either an EIF1AX (15, 48%) or a SF3B1 (9, 29%) mutation. Mutations in these genes were infrequent (2/35, 5.7%) in UMs with monosomy 3 (M3), which is the class associated with a poor prognosis. Re-sequencing of 13 UMs with loss of only parts of chomosome 3 (partM3) identified 8 tumors with a mutation in either SF3B1 (7, 54%) or EIF1AX (1, 8%). All EIF1AX mutations caused in-frame changes at the N-terminus and 17 of 19 SF3B1 mutations altered p.Arg625. Re-sequencing of 10 UMs with D3 that developed metastases (D3met) revealed a SF3B1 mutation in 3 tumors, however, none of them targeted p.Arg625.