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Nature:揭示引发髓母细胞瘤的遗传突变

来源:生物谷 2012-07-23 22:21

近日,来自斯坦福大学等处的研究者通过研究发现了常见的儿童脑瘤-髓母细胞瘤相关的基因突变,这就为相关的疾病治疗提供了一定的治疗建议,相关研究成果刊登在了国际著名杂志Nature上。

研究者Yoon表示,我们希望将髓母细胞瘤视为一种常见的疾病,而不是在分子水平来考虑如何治疗这种肿瘤。这种疾病起源于小脑,每年在美国影响很多儿童的健康,当前的疗法通过尽可能去除脑部的肿瘤来进行治疗,随后病人会进行发射化疗法,但是这种疗法并不是专门针对这种肿瘤的遗传特性的。

研究者从92份髓母细胞瘤中提取了其DNA,并且将提取出的DNA与相同病人的血型进行配对,随后研究者发现了12个遗传密码的点突变,这种突变在大脑中经常发生。其中有些突变在以前的髓母细胞瘤研究中发现过,但是有一些突变以前并没有发现过。其中有一种突变是在RNA解旋酶基因DDX3X上,研究者表示,这是髓母细胞瘤常见的第二大突变,而且目前在诸如慢性淋巴细胞白血病等疾病中也发现该基因的突变。

然而研究者表示,在不同的肿瘤病人中相同的基因突变很少,非常罕见。尽管没有单一的肿瘤同时携带了所发现的12种突变,但是研究者将其进行了分类,目前研究者表示他们可以理解为什么携带有特定遗传特性的特定肿瘤对标准的疗法具有极强的耐药性。2/3的髓母细胞瘤病人在诊断出疾病后仅仅能存活5年,许多病人经历着长期疗法所带来的物理和智力负面效应。

研究者Cho表示,其中一些突变可以影响细胞信号转导,因此,研究者表示,这些信号转导途径可以作为新的抗癌药物的新靶点,的确,以某种途径为靶点的药物目前正在进行临床前的研发。相关研究成果由国立健康中心支持。(生物谷Bioon.com)

编译自:Genetic Mutations That Cause Common Childhood Brain Tumors Identified

Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations

Trevor J. Pugh, Shyamal Dilhan Weeraratne, Tenley C. Archer, Daniel A. Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, Scott L. Carter, Kristian Cibulskis, Rachel L. Erlich, Heidi Greulich, Michael S. Lawrence, Niall J. Lennon, Aaron McKenna, James Meldrim, Alex H. Ramos, Michael G. Ross, Carsten Russ, Erica Shefler, Andrey Sivachenko, Brian Sogoloff, Petar Stojanov, Pablo Tamayo, Jill P. Mesirov, Vladimir Amani et al.

Medulloblastomas are the most common malignant brain tumours in children1. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles2, 3, 4, 5. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

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