美国转化基因组学研究所Jonathan J. Keats等研究人员合作发现，多发性骨髓瘤的全面分子分析确定精细的拷贝数和表达亚型。这一研究成果于2024年8月19日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，多发性骨髓瘤研究基金会的“将多发性骨髓瘤临床结果与个体基因组特征关联”研究（NCT01454297）是一项针对新诊断多发性骨髓瘤患者（n=1143）的纵向观察性临床研究，该研究在诊断和进展时对肿瘤样本进行全基因组测序、全外显子组测序和RNA测序，并每3个月收集临床数据。基线队列分析识别了因反复发生的功能获得和功能丧失事件而成为靶标的基因。

一致性聚类分析确定了8个独特的拷贝数亚型和12个独特的表达亚型，识别出高风险基因亚型，并揭示了这些独特生物学群体的许多分子基础。连续样本的分析显示，25.5%的患者在疾病进展时转变为高风险表达亚型。研究人员观察到在这一亚型中免疫治疗靶点的强烈表达，提示了一种潜在的治疗选择。

据悉，多发性骨髓瘤是一种可治疗但目前无法治愈的浆细胞血液恶性肿瘤，其肿瘤基因组具有多样性和复杂性，目前缺乏精准医疗的治疗方法。

附：英文原文

Title: Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes

Author: Skerget, Sheri, Penaherrera, Daniel, Chari, Ajai, Jagannath, Sundar, Siegel, David S., Vij, Ravi, Orloff, Gregory, Jakubowiak, Andrzej, Niesvizky, Ruben, Liles, Darla, Berdeja, Jesus, Levy, Moshe, Wolf, Jeffrey, Usmani, Saad Z., Christofferson, Austin W., Nasser, Sara, Aldrich, Jessica L., Legendre, Christophe, Benard, Brooks, Miller, Chase, Turner, Bryce, Kurdoglu, Ahmet, Washington, Megan, Yellapantula, Venkata, Adkins, Jonathan R., Cuyugan, Lori, Boateng, Martin, Helland, Adrienne, Kyman, Shari, McDonald, Jackie, Reiman, Rebecca, Stephenson, Kristi, Tassone, Erica, Blanski, Alex, Livermore, Brianne, Kirchhoff, Meghan, Rohrer, Daniel C., DAgostino, Mattia, Gamella, Manuela, Collison, Kimberly, Stumph, Jennifer, Kidd, Pam, Donnelly, Andrea, Zaugg, Barbara, Toone, Maureen, McBride, Kyle, DeRome, Mary, Rogers, Jennifer, Craig, David, Liang, Winnie S., Gutierrez, Norma C., Jewell, Scott D., Carpten, John, Anderson, Kenneth C., Cho, Hearn Jay, Auclair, Daniel, Lonial, Sagar, Keats, Jonathan J.

Issue&Volume: 2024-08-19

Abstract: Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study (NCT01454297) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n=1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

DOI: 10.1038/s41588-024-01853-0

Source: https://www.nature.com/articles/s41588-024-01853-0