通过全基因组关联分析，最常见的雌激素受体阳性乳腺癌易感突变已被确定，然而雌激素受体阴性乳腺癌易感突变尚不明确。全基因组关联分析是指在人类全基因组范围内找出存在的序列变异，即单核苷酸多态性，从中筛选出与疾病关联的单核苷酸多态性。

　　2017年10月23日，英国《自然》子刊《遗传学》在线发表全球470位科学家的联合研究报告，囊括了剑桥、牛津、哈佛、斯坦福、麻省理工、约翰霍普金斯等331家研究机构，正文共7页，作者姓名和所在机构名单共5页，研究方法共3页。

　　该研究对均为欧洲血统的国际乳腺癌研究联盟（BCAC）2万1468例雌激素受体阴性乳腺癌患者和10万594例对照者、国际乳腺癌易感基因突变研究者联盟（CIMBA）1万8908例BRCA1突变携带者（其中9414例乳腺癌患者）进行了全基因组关联分析。

　　结果在9个新的基因座确定10个突变与雌激素受体阴性乳腺癌独立关联（P<5×10-8）。基因座是一个基因或某些其他的DNA序列在染色体上所处的特定位置，每个基因座用染色体编号数、臂和其在染色体上所处位置表示，遗传连锁图可以显示染色体上基因座的排列顺序和彼此间的遗传图距。

　　此外，既往雌激素受体阴性乳腺癌或BRCA1突变携带者全基因组关联分析报道过11个乳腺癌风险关联突变，该研究重复了其中的10个关联（P<0.05），并观察到与其他研究确定的105个雌激素受体阴性乳腺癌易感突变关联一致。

　　上述125个突变可以阐明约16%的雌激素受体阴性乳腺癌家族风险。雌激素受体阴性乳腺癌风险与BRCA1突变携带者乳腺癌风险之间的遗传关联较高（0.72）。

　　因此，这些发现可能提高乳腺癌风险预测水平，提供更精细的定位，并更好地了解雌激素受体阴性乳腺癌的生物学基础。

Nat Genet. 2017 Oct 23. [Epub ahead of print]

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

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Cancer Council Victoria, Melbourne, Victoria, Australia; University of Melbourne, Melbourne, Victoria, Australia; University of Cambridge, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK; The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; University of Washington, Seattle, Washington, USA; Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; University of Toronto, Toronto, Ontario, Canada; Laval University, Québec City, Québec, Canada; Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Academic Medical Center, Amsterdam, the Netherlands; Johns Hopkins University, Baltimore, Maryland, USA; Chapel Allerton Hospital, Leeds, UK; Istituto Oncologico Veneto (IOV), IRCCS, Padua, Italy; University of Chicago, Chicago, Illinois, USA; University of Helsinki, Helsinki, Finland; Roswell Park Cancer Institute, Buffalo, New York, USA; Dartmouth College, Lebanon, New Hampshire, USA; Mount Sinai Hospital, Toronto, Ontario, Canada; University of California, Irvine, Irvine, California, USA; N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus; German Cancer Research Center (DKFZ), Heidelberg, Germany; Christian-Albrechts University Kiel, Kiel, Germany; Queen's University, Kingston, Ontario, Canada; Hannover Medical School, Hannover, Germany; Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA; University Medical Center Utrecht, Utrecht, the Netherlands; Istituto Nazionale dei Tumori (INT), Milan, Italy; McGill University, Montréal, Québec, Canada; University Hospital, Vall d'Hebron, Barcelona, Spain; Istituto Europeo di Oncologia, Milan, Italy; Batiment Cheney D, Centre Léon Bérard, Lyon, France; Landspitali, Reykjavik, Iceland; University of Iceland, Reykjavik, Iceland; Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany; Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Spanish National Cancer Centre (CNIO), Madrid, Spain; Spanish Network on Rare Diseases (CIBERER), Madrid, Spain; Ufa Scientific Center of the Russian Academy of Sciences, Ufa, Russian Federation; City of Hope, Duarte, California, USA; Université Clermont Auvergne, Clermont-Ferrand, France; Maastricht University Medical Center, Maastricht, the Netherlands; Vanderbilt University, Nashville, Tennessee, USA; International Epidemiology Institute, Rockville, Maryland, USA; Vesalius Research Center, VIB, Leuven, Belgium; University of Leuven, Leuven, Belgium; Vejle Hospital, Vejle, Denmark; Copenhagen University Hospital, Herlev, Denmark; University of Copenhagen, Copenhagen, Denmark; Oslo University, Oslo, Norway; National Institute of Oncology, Budapest, Hungary; University of Pennsylvania, Philadelphia, Pennsylvania, USA; Karolinska Institutet, Stockholm, Sweden; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; Gustave Roussy, Villejuif, France; Royal Devon and Exeter Hospital, Exeter, UK; National Cancer Institute, Rockville, Maryland, USA; Lund University, Lund, Sweden; BC Cancer Agency, Vancouver, British Columbia, Canada; Simon Fraser University, Burnaby, British Columbia, Canada; Catalan Institute of Oncology, Girona, Spain; Ruhr University Bochum, Bochum, Germany; University of Heidelberg, Heidelberg, Germany; Huntsman Cancer Institute, Salt Lake City, Utah, USA; CIBERONC, Hospital Clínico San Carlos, Madrid, Spain; University of Pisa and University Hospital of Pisa, Pisa, Italy; eter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Complejo Hospitalario Universitario de Santiago, Servizo Galego de Saúde SERGAS, Santiago de Compostela, Spain; Universidade de Santiago de Compostela, Santiago de Compostela, Spain; American Cancer Society, Atlanta, Georgia, USA; Instituto de Investigación Biomédica (IBI) de Orense-Pontevedra-Vigo, Xerencia de Xestión Integrada de Vigo, Servizo Galego de Saúde SERGAS, Vigo, Spain; Centre Francois Baclesse, Caen, France; Institut Curie, Paris, France - Université Paris Descartes, Sorbonne Paris Cité; University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hopital du Saint-Sacrement, Québec City, Québec, Canada; Ghent University, Ghent, Belgium; University of Sydney, Sydney, New South Wales, Australia; Sheffield Children's Hospital, Sheffield, UK; University Paris-Sud, Villejuif, France; University Paris-Saclay, Villejuif, France; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; CHU Arnaud de Villeneuve, Montpellier, France; University of Sheffield, Sheffield, UK; Imperial College London, London, UK; Cancer Research Center of Lyon, Lyon, France; Mayo Clinic, Rochester, Minnesota, USA; Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; South Glasgow University Hospitals, Glasgow, UK; Leiden University Medical Center, Leiden, the Netherlands; Vall d'Hebron University Hospital, Barcelona, Spain; Ludwig Maximilians University of Munich, Munich, Germany; University of Pretoria, Arcadia, South Africa; London School of Hygiene and Tropical Medicine, London, UK; University of Southampton, Southampton, UK; University of Westminster, London, UK; Institute of Human Genetics, University of Münster, Münster, Germany; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK; Lund University Hospital, Lund, Sweden; Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; University of Leipzig, Leipzig, Germany; Dijon University Hospital, Dijon, France; Oncogenetics, Centre Georges-Francois Leclerc, Dijon, France; University of California, Los Angeles, Los Angeles, California, USA; University of Edinburgh, Edinburgh, UK; The Institute of Cancer Research, London, UK; Chaim Sheba Medical Center, Ramat Gan, Israel; Tel Aviv University, Ramat Aviv, Israel; Curtin University, Perth, Western Australia, Australia; Memorial Sloan Kettering Cancer Center, New York, New York, USA; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; University Würzburg, Würzburg, Germany; University Hospital of Heraklion, Heraklion, Greece; Rigshospitalet, Copenhagen, Denmark; University of Kansas Medical Center, Kansas City, Kansas, USA; University of Utah, Salt Lake City, Utah, USA; Ohio State University James Comprehensive Cancer Center, Columbus, Ohio, USA; US National Institutes of Health, Bethesda, Maryland, USA; University of Oulu, Oulu, Finland; Pomeranian Medical University, Szczecin, Poland; Centre de Recherche du Centre Hospitalier de Université de Montréal (CHUM), Montréal, Québec, Canada; Medical University of Vienna, Vienna, Austria; University of Cologne, Cologne, Germany; University of Southern California, Los Angeles, California, USA; University of Massachusetts, Amherst, Amherst, Massachusetts, USA; Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; University of Eastern Finland, Kuopio, Finland; Kuopio University Hospital, Kuopio, Finland; Institute of Genetic Medicine, Centre for Life, Newcastle-upon-Tyne Hospitals NHS Trust, Newcastle-upon-Tyne, UK; University of Western Australia, Perth, Western Australia, Australia; National Cancer Institute, Bethesda, Maryland, USA; St George's, University of London, London, UK; Family Cancer Clinic, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois, USA; University of Chicago, Evanston, Illinois, USA; N.N. Petrov Institute of Oncology, St. Petersburg, Russian Federation; Georgetown University, Washington, DC, USA; National Cancer Center, Tokyo, Japan; Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; University of Ulm, Ulm, Germany; Aarhus University Hospital, Aarhus, Denmark; Cancer Prevention Institute of California, Fremont, California, USA; Stanford University, Stanford, California, USA; Seoul National University, Seoul, Republic of Korea; Technische Universitat Dresden, Dresden, Germany; National University of Ireland, Galway, Ireland; Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; University Hospitals Leuven, Leuven, Belgium; Bashkir State University, Ufa, Russian; National Centre for Scientific Research 'Demokritos', Athens, Greece; University of Oslo, Oslo, Norway; Odense University Hospital, Odense, Denmark; Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; University of Hong Kong, Hong Kong; Hong Kong Sanatorium and Hospital, Hong Kong; University Hospital of Region Zealand, Slagelse, Denmark; Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK; Clalit National Cancer Control Center, Haifa, Israel; Centre Léon Bérard, Lyon, France; Catalan Institute of Oncology, Barcelona, Spain; University of Hawaii Cancer Center, Honolulu, Hawaii, USA; University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea; Soonchunhyang University, Seoul, Republic of Korea; Institut Curie, Paris, France; PSL Research University, Paris, France; INSERM U900, Paris, France; Mines Paris Tech, Fontainebleau, France; Mayo Clinic, Scottsdale, Arizona, USA; M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; German Breast Group, Neu Isenburg, Germany; Macedonian Academy of Sciences and Arts, Skopje, Macedonia; University of California, San Diego, La Jolla, California, USA; Aichi Cancer Center Research Institute, Nagoya, Japan; Nagoya University, Nagoya, Japan; Lyon Neuroscience Research Center-CRNL, INSERM U1028, CNRS UMR 5292, University of Lyon, Lyon, France; Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia; VU University Medical Centre, Amsterdam, the Netherlands; Hospital Monte Naranco, Oviedo, Spain; National University of Singapore, Singapore; University of Manchester, Manchester, UK; Warwick University, Coventry, UK; University Health Network, Toronto, Ontario, Canada; Université Paris Sorbonne Cité, INSERM UMRS 1147, Paris, France; Heinrich Heine University Düsseldorf, Düsseldorf, Germany; University of California, San Francisco,San Francisco, California, USA; Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK; University of Groningen, Groningen, the Netherlands; University of New Mexico, Albuquerque, New Mexico, USA; University of Florence, Florence, Italy; Uppsala University, Uppsala, Sweden; Curtin University and University of Western Australia, Perth, Western Australia, Australia; Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; Portuguese Oncology Institute, Porto, Portugal; FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy; Moffitt Cancer Center, Tampa, Florida, USA; Western General Hospital, Edinburgh, UK; IDIBELL (Bellvitge Biomedical Research Institute), Barcelona, Spain; Northern Finland Laboratory Centre Oulu, Oulu, Finland; Karolinska University Hospital, Stockholm, Sweden; Carmel Medical Center and B. Rappaport Faculty of Medicine-Technion, Haifa, Israel; Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Hospital Universitario Puerta de Hierro, Madrid, Spain; Netherlands Cancer Institute, Amsterdam, the Netherlands; Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany; US National Institutes of Health, Research Triangle Park, North Carolina, USA; National Cancer Institute, Bangkok, Thailand; Case Western Reserve University, Cleveland, Ohio, USA; Guy's Hospital, King's College London, London, UK; John Hunter Hospital, Newcastle, New South Wales, Australia; University of Newcastle, Callaghan, New South Wales, Australia; Ohio State University, Columbus, Ohio, USA; China Medical University, Taichung, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Great Ormond Street Hospital for Children NHS Trust, London, UK; University of British Columbia, Vancouver, British Columbia, Canada; Saarland Cancer Registry, Saarbrücken, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; Cruces University Hospital and BioCruces Health Research Institute, Barakaldo, Spain; Cancer Research Malaysia, Subang Jaya, Malaysia; University Malaya Medical Centre, Kuala Lumpur, Malaysia; Columbia University, New York, New York, USA; University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Ospedale di Circolo ASST Settelaghi, Varese, Italy; Latvian Biomedical Research and Study Centre, Riga, Latvia; Addenbrooke's Hospital, Cambridge, UK; University of Oxford, Oxford, UK; Pontificia Universidad Javeriana, Bogotá, Colombia; Prince of Wales Hospital, Randwick, New South Wales, Australia; Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Frauenklinik der Stadtklinik Baden Baden, Baden Baden, Germany; Erasmus University Medical Center, Rotterdam, the Netherlands; IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Charite Berlin, Berlin, Germany; Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain; National Cancer Institute, Aviano, Italy; Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK; St. Jude Children's Research Hospital, Memphis, Tennessee, USA; University of California, San Francisco, San Francisco, California, USA; University of Porto, Porto, Portugal; University of Melbourne and the Royal Women's Hospital, Melbourne, Victoria, Australia; University La Sapienza, Rome, Italy; South General Hospital, Stockholm, Sweden; Technische Universitat München, Munich, Germany.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

PMID: 29058716

DOI: 10.1038/ng.3785