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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

机译：胰腺癌基因组揭示了轴突引导途径基因的异常

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摘要

这项大型研究发表了对142个“胰腺导管腺癌”rn(最常见的胰腺癌形式)患者所做的外显子组rn测序结果和版本数变异体分析结果。所获得的rn发现包括在染色质修饰和DNA损伤修复中所涉rn及的基因突变，这些突变以前并没有发现与该rn疾病有关。重要的是，这些数据显示，在Slitrn和Semaphorin信号作用中所涉及的基因的异rn常表达与患者存活率低有关，而且在动物模型rn中还与病情发展变化有关。%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 virro 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.
机译：这项大型研究发表了对142个“胰腺导管腺癌”rn(最常见的胰腺癌形式)患者所做的外显子组rn测序结果和版本数变异体分析结果。所获得的rn发现包括在染色质修饰和DNA损伤修复中所涉rn及的基因突变，这些突变以前并没有发现与该rn疾病有关。重要的是，这些数据显示，在Slitrn和Semaphorin信号作用中所涉及的基因的异rn常表达与患者存活率低有关，而且在动物模型rn中还与病情发展变化有关。%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 virro 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.

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  • 来源
    《Nature》 |2012年第7424期|p.399-405a3|共8页
  • 作者

    Andrew V. Biankin; Nicola Waddelr; Karin S. Kassahn; Marie-Claude Gingras; Lakshmi B. Muthuswamy; et al;

  • 作者单位

    The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street,Darlinghurst, Sydney, New South Wales 2010, Australia,Department of Surgery,Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200,Australia,Department of Surgery,Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200,Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia;

    Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA,Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411,USA;

    Ontario Institute for Cancer Research, Toronto M5G 0A3, Canada;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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