Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.
Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.
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DOI：
10.1016/s1470-2045(16)30240-6
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发表时间：
2016-10
期刊：
影响因子：
51.1
通讯作者：
Schumacher, Johannes
中科院分区：
文献类型：
--
作者：
Gharahkhani, Puya;Fitzgerald, Rebecca C.;Vaughan, Thomas L.;Palles, Claire;Gockel, Ines;Tomlinson, Ian;Buas, Matthew F.;May, Andrea;Gerges, Christian;Anders, Mario;Becker, Jessica;Kreuser, Nicole;Noder, Tania;Venerito, Marino;Veits, Lothar;Schmidt, Thomas;Manner, Hendrik;Schmidt, Claudia;Hess, Timo;Boehmer, Anne C.;Izbicki, Jakob R.;Hoelscher, Arnulf H.;Lang, Hauke;Lorenz, Dietmar;Schumacher, Brigitte;Hackelsberger, Andreas;Mayershofer, Rupert;Pech, Oliver;Vashist, Yogesh;Ott, Katja;Vieth, Michael;Weismueller, Josef;Noethen, Markus M.;Attwood, Stephen;Barr, Hugh;Chegwidden, Laura;de Caestecker, John;Harrison, Rebecca;Love, Sharon B.;MacDonald, David;Moayyedi, Paul;Prenen, Hans;Watson, R. G. Peter;Iyer, Prasad G.;Anderson, Lesley A.;Bernstein, Leslie;Chow, Wong-Ho;Hardie, Laura J.;Lagergren, Jesper;Liu, Geoffrey;Risch, Harvey A.;Wu, Anna H.;Ye, Weimin;Bird, Nigel C.;Shaheen, Nicholas J.;Gammon, Marilie D.;Corley, Douglas A.;Caldas, Carlos;Moebus, Susanne;Knapp, Michael;Peters, Wilbert H. M.;Neuhaus, Horst;Roesch, Thomas;Ell, Christian;MacGregor, Stuart;Pharoah, Paul;Whiteman, David C.;Jankowski, Janusz;Schumacher, Johannes
食管腺癌是高收入国家增长最快的癌症之一。Barrett食管是食管腺癌的癌前病变。然而，只有少数Barrett食管患者发展为腺癌，这在缺乏有效预测因素的情况下使临床管理复杂化。在一个研究Barrett食管和食管腺癌遗传学的国际联盟中，我们旨在确定Barrett食管和食管腺癌发生的新遗传风险变体。我们对PubMed中截至2016年2月29日的Barrett食管和食管腺癌的所有全基因组关联研究进行了荟萃分析;所有患者均为欧洲血统，疾病均经组织病理学证实。所有参与者均来自欧洲、北美和澳大利亚的四项独立研究，并在高密度单核苷酸多态性（SNP）阵列上进行基因分型。荟萃分析采用固定效应反向方差加权法和标准全基因组显著性阈值（p <5 × 10 − 8）进行。 我们还做了关联分析后，重新加权的基因座的方法，调查注释富集全基因组显着位点。此外，整个数据集进行了分析与生物信息学的方法，包括功能注释数据库和基于基因和基于路径的方法，以确定病理生理相关的细胞机制。我们的样本包括6167例Barrett食管患者和4112例食管腺癌患者，以及来自欧洲、北美和澳大利亚的4项全基因组关联研究的17159例代表性对照。 我们在CFTR基因内或附近发现了8个与Barrett食管或食管腺癌相关的新的风险位点，（rs17451754; p = 4·8 × 10 − 10），MSRA（rs17749155; p = 5·2 × 10 − 10）、LINC00208和BLK（rs10108511; p = 2·1 × 10 − 9），KHDRBS 2（rs62423175; p = 3·0 × 10 − 9）、TPPP和CEP 72（rs9918259; p = 3·2 × 10 − 9），TMOD 1（rs7852462; p = 1·5 × 10 − 8），SATB 2（rs139606545; p = 2.0 × 10 − 8），以及HTR3C和ABCC5（rs9823696; p = 1.6 × 10 − 8）。 在HTR3C和ABCC 5附近发现的基因座（rs9823696）与食管腺癌特异性相关（p = 1.6 × 10 − 8），与Barrett食管的发育无关（p = 0.45）。 第九个新的风险位点被确定在基因LPA（rs12207195;后验概率0.925）后，显着丰富的注释重新加权。确定的最强疾病途径（p <10 − 6）属于肌细胞分化和间充质发育和分化。我们对全基因组关联研究的荟萃分析使Barrett食管和食管腺癌的已知风险位点数量增加了一倍，并揭示了这些疾病原因的新见解。此外，食管腺癌与HTR3C和ABCC 5附近的位点之间的特异性关联可能构成预测Barrett食管向食管腺癌转变的新的遗传标记。新的风险位点的精细定位和功能研究可能会导致识别Barrett食管和食管腺癌发展中的关键分子，这可能会鼓励开发先进的预防和干预策略。美国国家癌症研究所、美国国立卫生研究院、澳大利亚国家卫生和医学研究理事会、瑞典癌症协会、英国医学研究理事会、剑桥NIHR生物医学研究中心、剑桥实验癌症医学中心、Else Kröner Fresenius Stiftung、惠康信托基金、英国癌症研究中心、英国阿斯利康、莱斯特大学医院、牛津大学、澳大利亚研究理事会。
Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.