来自美国、澳大利亚、加拿大的研究人员组成的一个国际研究小组报告了一项大规模胰腺癌基因组分析研究的结果,揭示了导致这一癌症潜在突变的复杂性,发现了与之相关的两条新信号途径。这些信息将推动开发出胰腺癌的新早期诊断测试。

-2012年11月15日《自然》

中文翻译


【题目】胰腺癌基因组揭示轴突导向通路基因中的畸变

【译文】胰腺癌是一种高度致命性恶性肿瘤,几乎没有有效的治疗方法。我们展开了外显子测序和拷贝数分析,以界定在早期(I和II期)散发胰腺导管腺癌的预期累积的临床队列(n = 142)中的基因组畸变。对99个已有资料肿瘤的细节分析鉴定了具有2016个非静息突变和1628个拷贝数突变的重大异质性。我们定义了16个显著突变的基因,并揭示了新的突变基因,包括参与染色体修饰(EPC1和ARID2)、DNA损伤修复(ATM)及其他机制(ZIM2、MAP2K4、NALCN、SLC16A4和MAGEA6)等基因。综合分析体外功能性数据和动物模型为这些遗传畸变在致癌中的潜在作用提供了支持性的证据。对再发性突变基因基于通路的分析概括了胰腺导管腺癌核心信号通路中成簇现象,并在每个通路中鉴定了新的突变基因。我们还在通常被描述为轴突导向的胚胎调控因子的基因中鉴定了频发的和不同的体细胞畸变,尤其是SLIT/ROBO信号通路,在胰腺癌鼠“睡美人”转座子介导的体细胞突变模型中也很明显,这提供了更有力的证据证实了轴突导向基因参与了胰腺致癌作用。

英文原稿


[Title]: Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

[Authors]:Andrew V. Biankin1, 2, 3 Nicola Waddell4 Karin S. Kassahn4 Marie-Claude Gingras5, 6 Lakshmi B. Muthuswamy7 Amber L. Johns1 David K. Miller4 Peter J. Wilson4 Ann-Marie Patch4 Jianmin Wu1 David K. Chang1, 2, 3 Mark J. Cowley1 Brooke B. Gardiner4 Sarah Song4 Ivon Harliwong4 Senel et al

[Abstract]Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

原文地址

http://www.nature.com/nature/journal/v491/n7424/full/nature11547.html

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