推荐活动

JAMA:全外显子组测序追踪找到了白血病复发的基因突变

首页 » 研究 » 肿瘤 2015-03-24 转化医学网 赞(3)
分享: 
导读
 近日,圣犹大儿童研究医院的研究人员对急性淋巴性白血病患者机体的基因组进行了精细的追踪,从而鉴别出了6个在疾病复发过程中极易突变的基因,分别为NT5C2, CREBBP, WHSC1,。。。

  近日,来自圣犹大儿童研究医院的研究人员发表在国际著名杂志Journal of the American Medical Association上的一篇研究论文中表示,他们已经使用了全外显子组测序对急性淋巴性白血病(Acute lymphoblastic leukemia,ALL)患者机体的基因组进行了精细的追踪,以此来寻找引发患者疾病复发的的遗传改变。

  诸如白血病在内的癌症并不是一种均一的疾病,在癌症中存在一系列不同的癌细胞分裂,这些分裂名为克隆,其均具有独特的突变;当化疗杀灭计划所有的克隆时,有些克隆或许就会逃脱疗法的作用,从而开始进行多重复制并且导致癌症复发。研究者Jinghui Zhang表示,我们在由少数癌症克隆引发的大多数疾病复发病例中研究分析发现,这些极少数的克隆往往会以极低水平存在,而且其可以免于疗法的杀灭作用而生存下来。

  大多数人会认为癌症克隆或许携带有很多突变使其易于在疗法及进化过程中存活,但事实似乎并不如此;在复发的肿瘤中,75%的肿瘤都是当初患者诊断时少数亚克隆的后代肿瘤组织,这就表明在大多数的情况下主要的优势癌症克隆或许往往易于被疗法所清除掉。文章中研究者利用全外显子组测序技术对ALL三个不同阶段的细胞样本进行癌症基因组突变的分析,三个阶段包括诊断、缓解及复发阶段,通过分析就可以帮助研究人员追踪癌症克隆的突变,而分析结果表明,在诊断和复发期患者机体中存在的突变存在较大的多样性,因此癌症细胞或许是在癌症发展过程中开始大范围突变的,同时研究人员还鉴别出了6个在疾病复发过程中极易突变的基因,分别为NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1。

  研究者表示,这项研究对于ALL的临床治疗具有非常重要的意义,由于癌细胞很多突变都和疗法耐药性直接相关,而且表观遗传调节子的高频率突变也将为潜在癌症药物靶点的开发提供新的研究线索。当前研究者正在努力去研究解析和ALL复发相关基因的生物学功能。(转化医学网360zhyx.com)

  以上为转化医学网原创翻译整理,如需转载,请联系 info@360zhyx.com
转化医学网推荐的新闻阅读:

Scientists have used whole-exome sequencing to detail the genomic changes that drove relapse in patients with acute lymphoblastic leukemia (ALL).

Cancers such as leukemia are not a homogeneous disease, but a jumble of different dividing cancer cells, called clones, with distinctive sets of mutations. While chemotherapy might kill almost all the clones, some might escape therapy, leaving them to multiply and cause relapse.

Led by Charles Mullighan and Jinghui Zhang of the St. Jude Children's Research Hospital and Stephen Hunger of the Children's Hospital of Philadelphia, the scientists showed that most cases of relapse were driven by minor clones present at extremely low levels that managed to survive therapy.

"This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn't seem to be the case," Zhang said in a statement.

Of the relapsed tumors, 75 percent of them were descendants of minor subclones at the time of diagnosis, suggesting that in most cases the predominant clones were eradicated by therapy.

The researchers used deep whole-exome sequencing to analyze the cancer genome mutations in cell samples taken at three stages of ALL, diagnosis, remission, and relapse, allowing them to track mutations in clones. The samples were taken from 20 children who had ALL that returned following treatment. ALL is a leading cause of cancer deaths in children, with 15 percent of ALL patients relapsing, St. Jude said.

Their analysis showed great diversity in mutations at both diagnosis and relapse, suggesting that cancer cells mutate wildly throughout cancer progression. They identified seven specific genes in six pathways that were highly likely to be mutated in relapsed disease: NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.

The findings have direct implications for the clinical management of ALL, the authors wrote. They suggested that there could be clinical utility to assaying for specific mutations that might predict relapse during the course of ALL treatment. Several mutations conferred resistance to therapeutics, they said, adding that a high frequency of mutations in epigenetic regulators suggested potential drug targets.

"When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone," Zhang, a co-senior author of the study, said. "We should also be tracking what kinds of mutations exist in the minor subclones."

Researchers at St. Jude and elsewhere are currently exploring the biological functions of the relapse-related genes......



评论:
评 论
共有 0 条评论

    还没有人评论,赶快抢个沙发

相关阅读