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Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, and single-nucleotide variants (SNVs). To enable integrative studies across these diverse mutation types, we developed a capture-based sequencing platform to detect their occurrence in 465 genes altered in MM and used it to sequence 95 primary tumor-normal pairs to a mean depth of 104×. We detected cases of hyperdiploidy (23%), deletions of 1p (8%), 6q (21%), 8p (17%), 14q (16%), 16q (22%), and 17p (4%), and amplification of 1q (19%). We also detected  IGH  and  MYC  translocations near expected frequencies and non-silent SNVs in  NRAS  (24%),  KRAS  (21%),  FAM46C  (17%),  TP53  (9%),  DIS3  (9%), and  BRAF  (3%). We discovered frequent mutations in  IGLL5  (18%) that were mutually exclusive of  RAS  mutations and associated with increased risk of disease progression ( p  = 0.03), suggesting that  IGLL5  may be a stratifying biomarker. We identified novel  IGLL5 / IGH  translocations in two samples. We subjected 15 of the pairs to ultra-deep sequencing (1259×) and found that although depth correlated with number of mutations detected ( p  = 0.001), depth past ~300× added little. The platform provides cost-effective genomic analysis for research and may be useful in individualizing treatment decisions in clinical settings.

A multiple myeloma-specific capture sequencing platform discovers novel translocations and frequent, risk-associated point mutations in IGLL5