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首页 » Cell报道 » Cell & NEJM:全球癌症基因组图谱计划又一研究突破 阐明致死性肾癌的发病机制

Cell & NEJM:全球癌症基因组图谱计划又一研究突破 阐明致死性肾癌的发病机制

来源:生物谷 2015-11-06 21:50

图片来源:france-oncology.com

2015年11月9日 讯 /生物谷BIOON/ --最近,发表在国际杂志the New England Journal of Medicine上的一篇研究论文中,来自从事癌症基因组图谱(The Cancer Genome Atlas)研究计划的科学家通过进行研究,对第二种常见类型的肾癌的两种类型进行了分子特性的分析,并且对这种常见类型的肾癌进行了不同的分类。

每年乳头状肾细胞癌 (Papillary renal cell carcinoma)在常见肾癌中的发病率就占到了15%至20%,长期以来这种肾癌被分为1型和2型,但研究者对于引发乳头状肾细胞癌发生的遗传和分子原因知之甚少,而正因为此也一直没有有效的疗法来帮助治疗乳头状肾细胞癌。

文章中,研究者Hui Shen博士表示,乳头状肾细胞癌为科学家们提出了一个特殊的问题,即在某些病人中,疾病虽然没有任何痛感,但却已经广泛扩散于患者的肾脏中了,而在其他病例中,单一的损伤或许是极度恶性的;本文研究中研究者不仅为临床医生们提供了其所需的基于临床结论的研究数据,而且还为开发新型靶向疗法来更好地治疗乳头状肾细胞癌亚型提供希望。

这项研究中,研究人员通过对161名患者的肿瘤组织进行基因组分析,结果发现1型和2型的乳头状肾细胞癌在分子和基因组上并不相同,而且可以被认为是两种完全分离不同的疾病,而2型的乳头状肾细胞癌也分为三种不同的亚型,每一种亚型都具有不同的分子改变和特性。其中一种2型乳头状肾细胞癌的主要特点为DNA甲基化或超甲基化的出现,DNA甲基化是DNA分子的一种修饰,其可以帮助控制基因被开启或关闭,一旦出任何差错就是导致肿瘤的发生;研究者指出,新型的2型乳头状肾细胞癌,即CpG岛甲基化表型是所有类型的头状肾细胞癌中总体存活率最低的亚型,而且这种亚型还和病人机体代谢基因直接改变相关,这些改变都会引发CpG岛甲基化表型肿瘤细胞经历代谢改变,从而促进肿瘤细胞快速生长并且保持活性。

研究者表示,CpG岛甲基化表型样本和乳头状肾细胞癌早期发生相关,而且是最具有致死性的,因此利用分子标志物有效地区分各种亚型的分子特性或可为科学家和临床医生们提供一种有力的工具对多种类型患者进行早期诊断,并且早日采取有效的措施来遏制疾病的发生。

本文的研究工作是癌症基因组图谱计划近日的又一力作,上个月该研究小组还在NEJM上发表了一篇分析乳腺浸润性小叶癌发生机制的研究论文,同日他们还在国际著名杂志Cell上发表了一篇文章,在Cell这篇文章中,研究人员阐明了前列腺癌发生的遗传背景。最后研究者Laird表示,癌症基因组图谱研究对于癌症研究的影响是不可估量的,该计划联合了成百上千名科学家们来进行大规模出色的癌症研究,相信通过后期大量的研究可以获取更多有效的数据来帮助指导临床上癌症的研究,同时也帮助开发新型的癌症疗法。(生物谷Bioon.com)

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The Molecular Taxonomy of Primary Prostate Cancer.

Cancer Genome Atlas Research Network. Electronic address: schultz@cbio.mskcc.org; Cancer Genome Atlas Research Network.

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

The Cancer Genome Atlas Research Network Group.

BACKGROUND Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2–antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.)

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