Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy.
Multiple Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida.
Clin Cancer Res. 2021 Dec 1;27(23):6479-6490. doi: 10.1158/1078-0432.CCR-20-4366. Epub 2021 Sep 15.
Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments.
We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the algorithm.
Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our DSS showed that not only t(11;14) but also chr(1q)gain/amps and inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax.
The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.
多发性骨髓瘤是一种生物学异质性浆细胞疾病。在这项研究中，我们旨在剖析基因突变、拷贝数异常（CNA）和染色体重排（CR）对转录组的功能影响。此外，我们应用基因转录组学方法来鉴定用于个体化治疗的特定生物标志物。
我们分析了 CoMMpass 研究的 IA12 版本中的 514 名新诊断患者，这些患者涉及多发性骨髓瘤驱动基因的突变、结构变异、拷贝数片段和原始转录本计数。我们进行了药物敏感性筛选（DSS），在使用算法将细胞系锚定到原发肿瘤样本后，对癌症依赖图谱（DepMap）数据集进行了查询。
免疫球蛋白易位、超二倍体和 chr(1q) 增益/扩增与最多数量的失调基因相关。其他 CNA 和特定基因突变的影响较低，但非常明显，影响特定途径。许多反复出现的基因表现出热点（HS）特异性效应。在我们的分析中，双打击多发性骨髓瘤的临床相关性具有坚实的生物学基础。肿瘤抑制基因的双等位基因缺失和 chr(1q) 扩增显示出对基因表达的最大影响，失调与细胞周期、增殖和免疫治疗靶点表达相关的途径。此外，我们的 DSS 表明，不仅 t(11;14)，而且 chr(1q) 增益/扩增和 失活也预测了 BCL2 轴转录本的差异表达和对 venetoclax 的反应。
多发性骨髓瘤的基因组结构和转录组之间存在严格的联系，由 CNA 和 CR 主导。基因突变尤其影响癌基因的 HS 突变和双等位基因肿瘤抑制基因失活。最后，全面的基因转录组学分析可以鉴定多发性骨髓瘤中特定失调途径和候选生物标志物，用于个体化治疗。
