Using gene-environment interactions to explore pathways for colorectal cancer risk.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-10-11 DOI:10.1016/j.ebiom.2025.105964

Emmanouil Bouras, Ren Yu, Andre E Kim, Georgios Markozannes, Neil Murphy, Demetrius Albanes, Laura N Anderson, Elizabeth L Barry, Sonja I Berndt, D Timothy Bishop, Hermann Brenner, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Andrew T Chan, Iona Cheng, Matthew A Devall, Virginia Diez-Obrero, Niki Dimou, David A Drew, Stephen B Gruber, Andrea Gsur, Michael Hoffmeister, Li Hsu, Jeroen R Huyghe, Eric Kawaguchi, Temitope O Keku, Anshul Kundaje, Sébastien Küry, Loïc Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M Lynch, Victor Moreno, John L Morrison, Christina C Newton, Mireia Obón-Santacana, Julie R Palmer, Nikos Papadimitriou, Andrew J Pellatt, Anita R Peoples, Paul D P Pharoah, Elizabeth A Platz, Conghui Qu, Edward Ruiz-Narvaez, Joel Sanchez Mendez, Robert E Schoen, Mariana C Stern, Claire E Thomas, Yu Tian, Caroline Y Um, Kala Visvanathan, Pavel Vodicka, Veronika Vymetalkova, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Marc J Gunter, W James Gauderman, Ulrike Peters, Marina Evangelou, Konstantinos K Tsilidis

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引用次数: 0

Abstract

Background: Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.

Methods: We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].

Findings: A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P < 0.05) for at least one exposure, as well as 1227 genes within the enriched pathways. Data were available for 811/1227 coding genes in the OTP, 241 of which were supported by strong relative abundance of prior evidence (overall OTP score > 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms.

Interpretation: The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies.

Funding: This study was funded by Cancer Research UK (CRUK; grant number:PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements.

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利用基因-环境相互作用探索结直肠癌风险的途径。

背景：结直肠癌（CRC）是一个重大的公共卫生问题，因此迫切需要确定新的干预目标来预防结直肠癌。方法：我们对15种存在CRC风险的暴露（体重指数、身高、体力活动、吸烟、2型糖尿病、使用绝经期激素治疗、非甾体抗炎药、摄入酒精、钙、纤维、叶酸、水果、加工肉类、红肉和蔬菜）进行了全基因组相互作用分析，并使用相互作用估计来探索CRC风险的途径和基因。贝叶斯因子的自适应组合（ADABF）和过度代表性分析（ORA）用于途径分析，并使用公共可用资源[癌症的标志，开放目标平台（OTP）]进一步调查研究结果。结果：在分析的2950个基因中，使用ADABF的共有1973个基因通路和使用ORA的840个基因通路在至少一次暴露中被富集（P < 0.05），在富集的基因通路中有1227个基因。共获得811/1227个OTP编码基因的数据，其中有241个基因具有较强的相对丰富的先验证据支持（OTP总评分为0.05）。50%的基因（617/1227）映射到至少一个癌症标志，其中大部分（388/617）与持续增殖信号标志有关。我们的发现反映了先前建立的结直肠癌风险途径，并强调了几个研究较少的基因的重要性。在几种暴露组合中发现了共同的途径，可能表明共同的潜在机制。解释：本分析结果为进一步的功能研究提供了基础。如果得到证实，它们可能有助于阐明危险因素与结直肠癌风险之间的病因学关联，并最终为个性化预防策略提供信息。资助：本研究由英国癌症研究中心（CRUK；批准号：PPRCPJT × 100005）和国际世界癌症研究基金会（WCRF; IIG_FULL_2020_022）资助。作为世界癌症研究基金国际资助项目的一部分，IIG_FULL_2020_022项目获得了Wereld Kanker Onderzoek基金会（WKOF）的资助。在致谢中提供了各个财团的完整资金细节。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.