Ram Meghana, Fraser Molly R, Vieira Dos Santos Junia, Tasakis Rafail, Islam Ariana, Abo-Donia Jannah Usama, Parekh Samir, Lagana Alessandro
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Broad Institute of MIT and Harvard, Boston, MA, USA.
Pharmgenomics Pers Med. 2024 Dec 21;17:573-609. doi: 10.2147/PGPM.S350238. eCollection 2024.
Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease's complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression.
This review was conducted through a state-of-The-art literature search, primarily utilizing PubMed to gather peer-reviewed articles. We focused on the most comprehensive and cited studies to ensure a thorough understanding of the genetic and molecular landscapes of MM.
We detail primary and secondary alterations such as translocations, hyperdiploidy, single nucleotide variants (SNVs), copy number alterations (CNAs), gene fusions, epigenetic modifications, non-coding RNAs, germline predisposing variants, and the influence of the tumor microenvironment (TME). Our analysis highlights the heterogeneity of MM and the challenges it poses in treatment and prognosis, emphasizing the distinction between driver mutations, which actively contribute to oncogenesis, and passenger mutations, which arise due to genomic instability and do not contribute to disease progression.
CONCLUSION & FUTURE PERSPECTIVES: We report key controversies and challenges in defining the genetic drivers of MM, and examine their implications for future therapeutic strategies. We discuss the importance of systems biology approaches in understanding the dependencies and interactions among these alterations, particularly highlighting the impact of double and triple-hit scenarios on disease outcomes. By advancing our understanding of the molecular drivers and their interactions, this review sets the stage for novel therapeutic targets and strategies, ultimately aiming to improve clinical outcomes in MM patients.
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征是骨髓内恶性浆细胞的克隆性增殖。该疾病的复杂性由多种驱动其进展的基因和分子异常所支撑。
本综述通过最先进的文献检索进行，主要利用PubMed收集同行评审的文章。我们专注于最全面且被引用最多的研究，以确保对MM的基因和分子格局有透彻的了解。
我们详细阐述了原发性和继发性改变，如易位、超二倍体、单核苷酸变异（SNV）、拷贝数改变（CNA）、基因融合、表观遗传修饰、非编码RNA、种系易感变异以及肿瘤微环境（TME）的影响。我们的分析突出了MM的异质性及其在治疗和预后方面带来的挑战，强调了驱动突变（积极促成肿瘤发生）与乘客突变（由于基因组不稳定而产生且对疾病进展无贡献）之间的区别。
我们报告了在确定MM的基因驱动因素方面的关键争议和挑战，并审视了它们对未来治疗策略的影响。我们讨论了系统生物学方法在理解这些改变之间的依赖性和相互作用方面的重要性，特别强调了双重打击和三重打击情况对疾病结局的影响。通过深化我们对分子驱动因素及其相互作用的理解，本综述为新型治疗靶点和策略奠定了基础，最终目标是改善MM患者的临床结局。
