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Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

Nature Genetics(2019)

Centre for Cancer Genetic Epidemiology | Centre de Bioinformatique | Department of Genetics and Computational Biology | Department of Epidemiology | Genomics Center | Program in Genetic Epidemiology and Statistical Genetics | Immunology and Molecular Oncology Unit | Department of Clinical Genetics | Human Genotyping-CEGEN Unit | Fred A. Litwin Center for Cancer Genetics | N.N. Alexandrov Research Institute of Oncology and Medical Radiology | Department of Pathology | Division of Clinical Epidemiology and Aging Research | Department of Public Health Sciences | Department of Breast Medical Oncology | Institute of Human Genetics | Cancer Prevention Program | Unit of Medical Genetics | High Risk and Cancer Prevention Group | Division of Epidemiology | Centro de Investigación en Red de Enfermedades Raras (CIBERER) | Institute of Biochemistry and Genetics | Department of Genetics and Pathology | Cancer Genetics and Prevention Program | Department of Oncology | Copenhagen General Population Study | Division of Cancer Prevention and Genetics | Institute of Medical Genetics and Applied Genomics | Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology | Sheffield Institute for Nucleic Acids (SInFoNiA) | Genome Sciences Centre | Institute for Prevention and Occupational Medicine of the German Social Accident Insurance | Molecular Epidemiology Group | Department of Medicine | Medical Oncology Department | Section of Molecular Genetics | Department of Internal Medicine | Research Department | Genomic Epidemiology Group | Cancer Research UK Cambridge Research Institute | Epidemiology Research Program | Oncology and Genetics Unit | CRCHU de Québec-oncologie | Department of Radiation Oncology | Departments of Pediatrics and Medicine | Centre for Medical Genetics | Westmead Institute for Medical Research | Department of Tumour Biology | Division of Molecular Pathology | Department of Laboratory Medicine and Pathology | Academic Unit of Pathology | Department of Medical Epidemiology and Biostatistics | Department of Population Sciences | Centre for Epidemiology and Biostatistics | Gynaecology Research Unit | Department of Non-Communicable Disease Epidemiology | Precision Medicine | Cáncer Hereditario | Southampton Clinical Trials Unit | Department of Biomedical Sciences | Cancer Sciences Academic Unit | Institute for Medical Informatics | Division of Evolution and Genomic Medicine | David Geffen School of Medicine | The Breast Cancer Now Toby Robins Research Centre | Leuven Multidisciplinary Breast Center | Department of Breast Surgery | Department of Cancer Epidemiology and Genetics | Program in Cancer Genetics | The Susanne Levy Gertner Oncogenetics Unit | School of Public Health | Genomic Medicine Group | Schools of Medicine and Public Health | Cancer Risk and Prevention Clinic | Department of Medical Oncology | Department of Pathology and Laboratory Medicine | Department of Dermatology | Human Cancer Genetics Programme | Clinical Genetics Branch | Department of Surgery | Centre de Recherche du Centre Hospitalier de Université de Montréal (CHUM) | Cancer & Environment Group | Center for Hereditary Breast and Ovarian Cancer | Department of Preventive Medicine | Institute of Environmental Medicine | Molecular Genetics of Breast Cancer | Translational Cancer Research Area | Saw Swee Hock School of Public Health | School of Population and Global Health | Family Cancer Clinic | Division of Cancer Sciences | Center for Medical Genetics | N.N. Petrov Institute of Oncology | Australian Breast Cancer Tissue Bank | The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) | Lombardi Comprehensive Cancer Center | Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’ | Sir Peter MacCallum Department of Oncology | Hematology | Division of Genetics and Epidemiology | Division of Cancer Epidemiology | Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute | Surgery | Department of Obstetrics and Gynecology | Familial Cancer Service | Radiation Epidemiology Branch | Molecular Diagnostics Laboratory | Division of Cancer Epidemiology and Genetics | Department of Histopathology and Cytology | Hong Kong Hereditary Breast Cancer Family Registry | Department of Electron Microscopy/Molecular Pathology and The Cyprus School of Molecular Medicine | VIB Center for Cancer Biology | Institut Curie | Department of Molecular Medicine and Surgery | Division of Health Sciences | Moores Cancer Center | Division of Molecular Medicine | Cancer Epidemiology Group | Anatomical Pathology | Department of Gynecology and Obstetrics | NRG Oncology | Department of Laboratory Medicine and Pathobiology | Radiation Oncology | Women’s College Research Institute | Department of Biochemistry and Molecular Medicine | Center for Genomic Medicine | Latvian Biomedical Research and Study Centre | Department of Health Sciences Research | Clinical Genetics Research Lab | Department of Molecular Genetics | Center for Clinical Cancer Genetics | Department of Cancer Epidemiology | Centre for Cancer Research and Cell Biology | University of New Mexico Health Sciences Center | Cancer Research UK Clinical Trials Unit | Section of Molecular Diagnostics | Genome Diagnostics Program | Department of Genetics and Fundamental Medicine | Translational Research Laboratory | Laboratory of Cancer Genetics and Tumor Biology | Unit of Molecular Bases of Genetic Risk and Genetic Testing | School of Women’s and Children’s Health | Clinical Genetics | Clinical Genetics Service | Clalit National Cancer Control Center | Chronic Disease Epidemiology | Epidemiology Branch | School of Medicine | Research Oncology | Molecular Biology of Breast Cancer | Clinical Cancer Genetics Program | Institute of Biomedical Sciences | Dept of OB/GYN and Comprehensive Cancer Center | Clinical Cancer Genetics | Ss. Cyril and Methodius University in Skopje | Population Oncology | Dept of OB/GYN | Faculty of Medicine | Department of Genetics | Cancer Research Malaysia | Genetic Counseling Unit | UO Anatomia Patologica | Department of Cancer Biology and Genetics | Institute of Cancer and Genomic Sciences | Center for Population Health Research | Frauenklinik der Stadtklinik Baden-Baden | Department of Health Science Research | Division of Functional onco-genomics and genetics | Biostatistics and Computational Biology Branch | Department of Clinical Science and Education | Department of Cancer Genetics

Cited 12|Views70
Abstract
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.
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要点】:本研究通过精细映射150个乳腺癌风险区域,识别出178个高置信度的目标基因,揭示了这些基因与乳腺癌风险之间的关联。

方法】:研究结合了关联分析、基因调控特征注释以及贝叶斯方法(PAINTOR)来确定具有高后验概率的因果变异。

实验】:研究使用了INQUSIT管道对基因进行优先排序,结合了基因表达(eQTL)、染色质相互作用和功能注释,实验结果在已知癌症驱动基因、转录因子以及发育、凋亡、免疫系统和DNA完整性检查点基因本体路径中发现了显著超表达的178个高置信度目标基因。数据集名称未在论文中提及。