遗传突变检测或可帮助改善骨髓瘤疗法

  发表于国际杂志Journal of Clinical Oncology上的一篇研究论文中，来自英国伦敦癌症研究院的科学家们表示，对遗传风险因子的检测或可帮助改善骨髓瘤的疗法，同时也可以帮助医生们鉴别出那些患恶性骨髓瘤的患者。研究者指出，我们发现9种遗传特征需要被检测来帮助鉴别可以从强化治疗过程中获益的高风险患者。
  该研究由英国伦敦癌症研究院等机构提供资助，文章中研究者首次揭示了骨髓瘤细胞的遗传突变和个体生存率之间的关联；研究者利用遗传测序技术对黑色素瘤XI临床试验中招募的463名患者进行了分析，最终鉴别出了15个基因在多个骨髓瘤亚型患者中发生了明显的突变，同时研究者还进行了绘图来阐明这些基因突变和个体长期生存率之间的关系。
  研究者表示，对9种突变基因的检测同确定个体骨髓瘤等级的检测手段进行结合，就可以鉴别出90%因恶性癌症而过早死亡的患者；携带突变的骨髓瘤患者机体中会存在一种名为CCND1的基因，该基因可以控制癌细胞的分裂，相比不携带该基因的个体而言，携带该基因的个体往往更易患多种类型的疾病，仅有38%的CCND1突变的患者生存期超过了2年。
  DNA修复基因TP53在将近11%的骨髓瘤患者机体中都是缺失的，而这就和患者生存期较短直接相关，仅有54%的TP53突变患者的生存超过了2年；骨髓瘤中常见的遗传缺失就是RAS基因家族成员的突变，其中一个基因就是ICR基因，该基因在很多癌症中都处于缺失状态，而研究者又发现NRAS和KRAS基因在43%的患者中处于突变状态，这就表明，骨髓瘤RAS突变可以驱动细胞癌性化，同时也为开发新型靶向疗法提供了依据。
  最后研究者Paul Workman教授指出，如今我们可以利用特殊的检测手段对一系列特殊的突变进行检测，这就可以帮助我们寻找那些更易于发生癌症恶化的患者，同时这些患者也需要进行强化治疗来增加其生存率；本文研究同时也为开发治疗骨髓瘤的靶向疗法提供了新的希望和帮助。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma
JCO    doi: 10.1200/JCO.2014.59.1503
Brian A. Walker, Eileen M. Boyle, Christopher P. Wardell, Alex Murison, Dil B. Begum, Nasrin M. Dahir, Paula Z. Proszek, David C. Johnson, Martin F. Kaiser, Lorenzo Melchor, Lauren I. Aronson, Matthew Scales, Charlotte Pawlyn, Fabio Mirabella, John R. Jones, Annamaria Brioli, Aneta Mikulasova, David A. Cairns, Walter M. Gregory, Ana Quartilho, Mark T. Drayson, Nigel Russell, Gordon Cook, Graham H. Jackson, Xavier Leleu, Faith E. Davies and Gareth J. Morgan⇑
Purpose At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established.

Methods We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available.

Results We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely.

Conclusion We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.