Boyle Eileen M, Blaney Patrick, Stoeckle James H, Wang Yubao, Ghamlouch Hussein, Gagler Dylan, Braunstein Marc, Williams Louis, Tenenbaum Avital, Siegel Ariel, Chen Xiaoyi, Varma Gaurav, Avigan Jason, Li Alexander, Jinsi Monica, Kaminetzsky David, Arbini Arnaldo, Montes Lydia, Corre Jill, Rustad Even H, Landgren Ola, Maura Francesco, Walker Brian A, Bauer Michael, Bruno Benedetto, Tsirigos Aristotelis, Davies Faith E, Morgan Gareth J
Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
Applied Bioinformatics Laboratories, NYU Langone Medical Center, New York, New York.
Clin Cancer Res. 2023 Oct 2;29(19):3901-3913. doi: 10.1158/1078-0432.CCR-22-3209.
Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown.
A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization.
We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants.
Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
1号染色体（chr1）的拷贝数异常（CNA）和结构变异（SV）在新诊断的多发性骨髓瘤（NDMM）中很常见，并且对预后有不同的影响，其驱动因素大多未知。
采用了一种多组学方法，包括CRISPR、CNA和SV的基因定位、甲基化、表达及突变分析，以记录chr1分子变异的程度及其对通路利用的影响。
我们确定了两组不同的1q增益：与有限的基因表达变化和中性预后相关的局灶性增益，以及与大量基因表达变化、复杂遗传学和不良预后相关的整条臂增益。CRISPR确定了一些对chr1的依赖性，但与获得性CNA相关的变异有限。我们确定了七个缺失区域、九个增益区域、三个染色体碎裂（CT）区域和两个模板插入（TI）区域，其中包含许多潜在驱动因素。另一种涉及1q基因低甲基化的机制可能导致许多基因的异常基因表达。与整条臂增益相关的表达变化很大，基因集富集分析确定代谢过程、凋亡抗性、通过MAPK途径的信号传导以及转录因子的上调是与这些变异相关的不良预后的关键驱动因素。
多层遗传复杂性影响与chr1上CNA相关的表型，从而产生其相关的临床表型。1q的整条臂增益是至关重要的预后组，它会使多种通路失调，这可能提供治疗靶点。
