文章：

多发性骨髓瘤特异性捕获测序平台发现IGLL5中的新型易位和频繁、风险相关的点突变

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

原文发布日期：2018-03-21

DOI: 10.1038/s41408-018-0062-y

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

多发性骨髓瘤（MM）是一种涉及拷贝数变异（CNV）、染色体易位和单核苷酸变异（SNV）的疾病。为整合这些不同突变类型的综合研究，我们开发了一种基于捕获的测序平台，用于检测465个MM相关基因中的突变，并对95对原发肿瘤-正常组织样本进行了平均深度为104倍的测序。我们检测到超二倍体（23%）、1p缺失（8%）、6q缺失（21%）、8p缺失（17%）、14q缺失（16%）、16q缺失（22%）和17p缺失（4%），以及1q扩增（19%）。同时检测到预期频率附近的IGH和MYC易位，以及NRAS（24%）、KRAS（21%）、FAM46C（17%）、TP53（9%）、DIS3（9%）和BRAF（3%）的非沉默SNV。我们发现IGLL5的频繁突变（18%）与RAS突变相互排斥，且与疾病进展风险增加相关（p=0.03），提示IGLL5可能作为分层生物标志物。在两个样本中首次发现IGLL5/IGH新型易位。对其中15对样本进行超深度测序（1259倍）后发现，尽管测序深度与检测到的突变数量相关（p=0.001），但超过约300倍深度后增益有限。该平台为研究提供了经济高效的基因组分析方案，并可能有助于临床治疗决策的个体化。

原文链接：

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