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

作者：White Brian S; Lanc Irena; O'Neal Julie; Gupta Harshath; Fulton Robert S; Schmidt Heather; Fronick Catrina; Belter Edward A Jr; Fiala Mark; King Justin; Ahmann Greg J; DeRome Mary; Mardis Elaine R; Vij Ravi; DiPersio John F; Levy Joan; Auclair Daniel; Tomasson Michael H^*

来源：Blood Cancer Journal, 2018, 8(3): 35.

DOI：10.1038/s41408-018-0062-y

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 104x. 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 (1259x) and found that although depth correlated with number of mutations detected (p = 0.001), depth past similar to 300x added little. The platform provides cost-effective genomic analysis for research and may be useful in individualizing treatment decisions in clinical settings.

• 出版日期2018-3-21