Characterizing the effects of cis-regulatory variation on patient outcomes and treatment response in Multiple Myeloma

摘要 多发性骨髓瘤(MM)是一种浆细胞的恶性肿瘤，是第二常见的血液系统肿瘤 占癌症死亡人数的2%。多发性骨髓瘤与预后不良有关，尽管新的治疗方法 虽然存活率有所提高，但大多数患者仍会复发。MM表现出很强的遗传性 多发性骨髓瘤患者的亲属罹患多发性骨髓瘤的风险要高出两到四倍。此外， 多发性骨髓瘤的发病率和死亡率在性别上存在差异，男性的风险高于女性。 全基因组关联研究(GWASs)和 Meta分析位于调控区域内或邻近区域，表明在转录中发挥作用 监管。然而，这些风险基因如何影响肿瘤的病因、进展和预后尚不清楚。 明白了。为加速发现多发性骨髓瘤患者的新疗法，多发性骨髓瘤研究 基金会(MMRF)开发了纵向CommPass研究。这项工作由乔纳森·济慈博士领导， TGen利用体细胞突变和转录谱鉴定了新的MM亚型。尽管如此， 影响患者预后的基因调控背后的遗传结构尚未得到研究。vbl.使用 在Commpass数据中，我们确定了7,737个与基因表达(表达)变化相关的变体 其中1,764个是雄性特有的，847个是雌性特有的eQTL。 此外，1,034个已识别的eQTL与Commpass队列中的存活率有关。然而， 功能验证对于确认监管效果和更好地评估功能后果是必要的 这一变种。为此，我建议使用多路高通量CRISPR激活剂/干扰 (CRISPRa/I)筛选，然后进行单细胞RNA测序，以验证推测的顺式调节基因座在 基因表达水平。为了确定这些基因是如何调节肿瘤病因学的，我将对 这些扰动对肿瘤适合性和治疗反应的影响。拟议的研究将提供 对多发性骨髓瘤发生、发展和应对背后的监管环境的有价值的见解 治疗，以及为多发性骨髓瘤患者开发更有针对性的治疗方法的潜在候选者。此外， 我将在这项研究中接受的癌症遗传学和癌症基因组学培训将为 作为一名独立调查员，我未来的研究方向。

ABSTRACT Multiple Myeloma (MM) is a malignancy of plasma cells and the second most common hematological cancer accounting for 2% of cancer deaths. MM is associated with a poor prognosis, and while new therapies have improved survival rates, most patients still experience relapses. MM shows a strong hereditary genetic component as relatives of MM patients have a two- to four-fold higher risk of disease development. Moreover, MM displays a disparity in occurrence and mortality among sexes with males having a higher risk than females. Many risk loci associated with MM susceptibility identified by genome-wide association studies (GWAS) and meta-analysis are located within or adjacent to the regulatory regions, indicating a role in transcriptional regulation. However, how these risk loci contribute to tumor etiology, progression and outcome are poorly understood. To accelerate the discovery of novel treatments for MM patients, the Multiple Myeloma Research Foundation’s (MMRF) developed the longitudinal CoMMpass study. This work, led by Dr. Jonathan Keats at TGen, has identified novel MM subtypes using somatic mutation and transcription profile. Nevertheless, the genetic architecture underlying gene regulation contributing to patient outcomes has not been examined. Using the CoMMpass data, we identified 7,737 variants associated with changes in gene expression (expression quantitative trait locus; eQTL); among these 1,764 are male-specific and 847 are female-specific eQTLs. Furthermore, 1,034 of the identified eQTLs are associated with survival in the CoMMpass cohort. However, functional validation is necessary to confirm the regulatory effects and better assess the functional consequences of this variation. To this end, I propose using a multiplex high throughput CRISPR activator/interference (CRISPRa/i) screen followed by single-cell RNA sequencing to validate the role of putative cis-regulatory loci on gene expression levels. To determine how these loci modulate tumor etiology, I will perform assays investigating the effects of these perturbations on tumor fitness and response to treatment. The proposed study will provide valuable insights into the regulatory landscape underlying MM occurrence, progression, and response to treatment, and potential candidates for developing more targeted treatments for MM patients. Furthermore, the training I will receive in this study on cancer genetics and cancer genomics will open up new opportunities for my future research directions as an independent investigator.