种系又称胚系或生殖系，是能够繁殖后代的细胞总称，包括单倍体配子（精子、卵子）以及最终能分化成配子的原始生殖细胞。种系变异对乳腺癌所致死亡的影响尚存争议。

　　2019年2月21日，英国癌症研究基金会和英国《自然》旗下《英国癌症杂志》在线发表荷兰、英国、德国、澳大利亚、加拿大、美国、西班牙、俄罗斯、芬兰、瑞典、比利时、丹麦、意大利、挪威、沙特阿拉伯、法国、希腊、波兰、爱尔兰、以色列、葡萄牙、哥伦比亚、中国天津医科大学天津市肿瘤医院肿瘤研究所的全基因组关联研究报告，通过大型荟萃分析调查了种系变异与乳腺癌所致死亡之间的相关性。

　　该研究根据多因素比例风险回归模型，对12组大样本数据、9万6661例乳腺癌女性、7697例乳腺癌所致死亡、大约1040万个变异进行荟萃分析。对6万4171例雌激素受体阳性、1万6172雌激素受体阴性乳腺癌患者（其中乳腺癌所致死亡分别为4116例、2125例）进行雌激素受体相关性分析。利用贝叶斯假发现概率（BFDP）对真阳性概率进行评估，预设P<5×10-8为显著相关。

　　结果，未发现任何与乳腺癌所致死亡显著相关的种系变异。

• 对于雌激素受体阳性乳腺癌，与乳腺癌所致死亡相关性最高的种系变异为7号染色体rs4717568（BFDP：7%，P=1.28×10-7，风险比：0.88，95%置信区间：0.84～0.92），靠近AUTS2基因。

• 对于雌激素受体阴性乳腺癌，与乳腺癌所致死亡相关性最高的种系变异为7号染色体rs67918676（BFDP：11%，P=1.38×10-7，风险比：1.27，95%置信区间：1.16～1.39），位于基因间长链非编码RNA基因AC004009.3内，靠近HOXA基因簇。

　　因此，该研究结果表明，7号染色体BFDP<15%的种系变异靠近有生物学证据与乳腺癌结局相关的基因。不过，全基因组关联分析未发现与乳腺癌所致死亡显著相关的种系变异，无法为乳腺癌患者提供个体化基因预后信息。

Br J Cancer. 2019 Feb 21. [Epub ahead of print]

Genome-wide association study of germline variants and breast cancer-specific mortality.

Maria Escala-Garcia, Qi Guo, Thilo Dork, Sander Canisius, Renske Keeman, Joe Dennis, Jonathan Beesley, Julie Lecarpentier, Manjeet K. Bolla, Qin Wang, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Bram Boeckx, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Borresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W. Brock, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ting-Yuan David Cheng, Suet-Feung Chin, Christine L. Clarke, Emilie Cordina-Duverger, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Helena M. Earl, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Eva Galle, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnaes, Mervi Grip, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Hakansson, Per Hall, Ute Hamann, Susan Hankinson, Elaine F. Harkness, Patricia A. Harrington, Steven N. Hart, Jaana M. Hartikainen, Alexander Hein, Peter Hillemanns, Louise Hiller, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Wolfgang Janni, Esther M. John, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Cari M. Kitahara, Julia A. Knight, Yon-Dschun Ko, Linetta B. Koppert, Veli-Matti Kosma, Peter Kraft, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Lian Li, Annika Lindblom, Sara Lindstrom, Martha Linet, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Melanie Maierthaler, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Pooja Middha, Nicola Miller, Roger L. Milne, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Rami Nassir, Susan L. Neuhausen, William T. Newman, Sune F. Nielsen, Borge G. Nordestgaard, Aaron Norman, Hakan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Christos Petridis, Mila Pinchev, Karoliona Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofieva, Katri Pylkas, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Emmanouil Saloustros, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Lukas Schwentner, Rodney J. Scott, Christopher Scott, Caroline Seynaeve, Mitul Shah, Jacques Simard, Ann Smeets, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Aline Talhouk, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Maria Tengstrom, Mary Beth Terry, Kathrin Thone, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Constance Turman, Clare Turnbull, Hans-Ulrich Ulmer, Michael Untch, Celine Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elke M. van Veen, Camilla Wendt, Alice S. Whittemore, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Yan Zhang, Douglas F. Easton, Peter A. Fasching, Heli Nevanlinna, Diana M. Eccles, Paul D. P. Pharoah, Marjanka K. Schmidt.

The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; University of Cambridge, Cambridge, UK; Hannover Medical School, Hannover, Germany; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Cambridge Experimental Cancer Medicine Centre, Cambridge, UK; Mount Sinai Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; University of California Irvine, Irvine, CA, USA; German Cancer Research Center (DKFZ), Heidelberg, Germany; Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Wisconsin-Milwaukee, Milwaukee, WI, USA; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia; City of Hope, Duarte, CA, USA; University of Helsinki, Helsinki, Finland; Orebro University, Orebro, Sweden; Vlaams Instituut voor Biotechnologie, Leuven, Belgium; University of Leuven, Leuven, Belgium; Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark; University of Copenhagen, Copenhagen, Denmark; European Institute of Oncology IRCCS Milan, Milan, Italy; Oslo University, Oslo, Norway; University of Oslo, Oslo, Norway; Vestre Viken Hospital, Drammen, Norway; Akershus University, Lorenskog, Norway; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; Queen Mary University of London, London, UK; National Cancer Institute, Bethesda, MD, USA; Lund University, Lund, Sweden; University of Sheffield, Sheffield, UK; University of Heidelberg, Heidelberg, Germany; The Institute of Cancer Research, London, UK; Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Hospital Cl'nico San Carlos, Madrid, Spain; University of Pisa, Pisa, Italy; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Universidad de Santiago de Compostela, Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago De Compostela, Spain; King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; American Cancer Society, Atlanta, GA, USA; Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain; University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Roswell Park Cancer Institute, Buffalo, NY, USA; University of Sydney, Sydney, NSW, Australia; University Paris-Sud, University Paris-Saclay, Villejuif, France; Mayo Clinic, Rochester, MN, USA; Imperial College London, London, UK; Cancer Research Center of Lyon, Lyon, France; Karolinska Institutet, Stockholm, Sweden; Fox Chase Cancer Center, Philadelphia, PA, USA; Leiden University, Leiden, The Netherlands; University of Warwick, Coventry, UK; University of Southampton, Southampton, UK; University of Westminster, London, UK; Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA; University of Leipzig, Leipzig, Germany; University of Manchester, Manchester, UK; St Marys Hospital, Manchester, UK; The University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, Edinburgh, UK; University of California San Diego, La Jolla, CA, USA; The Royal Marsden NHS Foundation Trust, London, UK; University Hospital of Heraklion, Heraklion, Greece; Cancer Council Victoria, Melbourne, VIC, Australia; The University of Melbourne, Melbourne, VIC, Australia; Monash University, Melbourne, VIC, Australia; University of Utah, Salt Lake City, UT, USA; University of Oulu, Oulu, Finland; University of Cologne, Cologne, Germany; University of Southern California, Los Angeles, CA, USA; South General Hospital, Stockholm, Sweden; German Cancer Research Centre (DKFZ), Heidelberg, Germany; University of Massachusetts, Amherst, MA, USA; Wythenshawe Hospital, Manchester, UK; University of Eastern Finland, Kuopio, Finland; Kuopio University, Kuopio, Finland; Saarland Cancer Registry, Saarbruecken, Germany; Erasmus MC Cancer Institute, Rotterdam, The Netherlands; University of Oxford, Oxford, UK; Cancer Prevention Institute of California, Fremont, CA, USA; Stanford University, Stanford, CA, USA; Tampere University, Tampere, Finland; Pomeranian Medical University, Szczecin, Poland; National University of Ireland, Galway, Ireland; Bashkir State University, Ufa, Russia; Johanniter Krankenhaus, Evangelische Kliniken Bonn gGmbH, Bonn, Germany; University of Hawaii, Honolulu, HI, USA; Carmel Medical Center and Technion, Clalit National Cancer Control Center, Haifa, Israel; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; University of Washington, Seattle, WA, USA; M. Sklodowska-Curie Cancer Centre, Warsaw, Poland; GmbH, German Breast Group, Neu Isenburg, Germany; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy; The Alfred Hospital, Melbourne, VIC, Australia; Ludwig Maximilian University of Munich, Munich, Germany; University Health Network, Toronto, ON, Canada; Université Paris Sorbonne Cité, Paris, France; University of California Davis, Davis, CA, USA; Queen's University Belfast, Belfast, Ireland, UK; University of New Mexico, Albuquerque, NM, USA; Hospital Monte Naranco, Servicio de Cirug'a General y Especialidades, Oviedo, Spain; Hospital Universitario Puerta de Hierro, Madrid, Spain; The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, IFOM, Milan, Italy; King's College London, London, UK; Northern Finland Laboratory Centre Oulu, Oulu, Finland; UCLH Foundation Trust, London, UK; University Hospital of Larissa, Larissa, Greece; Case Western Reserve University, Cleveland, OH, USA; John Hunter Hospital, Newcastle, NSW, Australia; University of Newcastle, Newcastle, NSW, Australia; Centre Hospitalier Universitaire de Québec - Université Laval Research Centre, Québec City, QC, Canada; University Hospitals Leuven, Leuven, Belgium; Monash University, Clayton, VIC, Australia; BC Cancer Agency and University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada; Portuguese Oncology Institute, Porto, Portugal; University of Porto, Porto, Portugal; Kuopio University Hospital, Cancer Centre, Kuopio, Finland; Columbia University, New York, NY, USA; University of Birmingham, Birmingham, UK; Pontificia Universidad Javeriana, Bogota, Colombia; Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany; Helios Clinics Berlin-Buch, Berlin, Germany; Erasmus University Medical Centre, Rotterdam, The Netherlands; University of California at Los Angeles, Los Angeles, CA, USA.

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

RESULTS: We did not find any variant associated with breast cancer-specific mortality at P<5×10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP=7%, P=1.28×10-7, hazard ratio [HR]=0.88, 95% confidence interval [CI]=0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP=11%, P=1.38×10-7, HR=1.27, 95% CI=1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP<15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

DOI: 10.1038/s41416-019-0393-x

以下广告内容与本微信公众号无关