Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
Authors: Liu Jingjing , Prager - van der Smissen Wendy J. C. , Collée J. Margriet , Bolla Manjeet K. , Wang Qin , Michailidou Kyriaki , Dennis Joe , Ahearn Thomas U. , Aittomäki Kristiina , Ambrosone Christine B. , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Arndt Volker , Arnold Norbert , Aronson Kristan J. , Augustinsson Annelie , Auvinen Päivi , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Bermisheva Marina , Bernstein Leslie , Bogdanova Natalia V. , Bogdanova-Markov Nadja , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Briceno Ignacio , Brucker Sara Y. , Brüning Thomas , Burwinkel Barbara , Cai Qiuyin , Cai Hui , Campa Daniele , Canzian Federico , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Choi Ji-Yeob , Christiaens Melissa , Clarke Christine L. ,   NBCS Collaborators, Sahlberg Kristine K. , Børresen-Dale Anne-Lise , Ottestad Lars , Kåresen Rolf , Schlichting Ellen , Holmen Marit Muri , Sauer Toril , Haakensen Vilde , Engebråten Olav , Naume Bjørn , Fosså Alexander , Kiserud Cecile E. , Reinertsen Kristin V. , Helland Åslaug , Riis Margit , Geisler Jürgen ,   OSBREAC, Bathen Tone F. , Borgen Elin , Fritzman Britt , Garred Øystein , Geitvik Gry Aarum , Hofvind Solveig , Langerød Anita , Lingjærde Ole Christian , Mælandsmo Gunhild Mari , Russnes Hege G , Skjerven Helle Kristine , Sørlie Therese , Alnæs Grethe I. Grenaker , Couch Fergus J. , Czene Kamila , Daly Mary B. , Devilee Peter , dos-Santos-Silva Isabel , Dwek Miriam , Eccles Diana M. , Eliassen A. Heather , Fasching Peter A. , Figueroa Jonine , Flyger Henrik , Fritschi Lin , Gago-Dominguez Manuela , Gapstur Susan M. , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Giles Graham G. , Goldberg Mark S. , Goldgar David E. , Guénel Pascal , Haiman Christopher A. , Håkansson Niclas , Hall Per , Harrington Patricia A. , Hart Steven N. , Hartman Mikael , Hillemanns Peter , Hopper John L. , Hou Ming-Feng , Hunter David J. , Huo Dezheng ,   ABCTB Investigators, Clarke Christine , Marsh Deborah , Scott Rodney , Baxter Robert , Yip Desmond , Carpenter Jane , Davis Alison , Pathmanathan Nirmala , Simpson Peter , Graham Dinny , Sachchithananthan Mythily , Ito Hidemi , Iwasaki Motoki , Jakimovska Milena , Jakubowska Anna , John Esther M. , Kaaks Rudolf , Kang Daehee , Keeman Renske , Khusnutdinova Elza , Kim Sung-Won , Kraft Peter , Kristensen Vessela N. , Kurian Allison W. , Le Marchand Loic , Li Jingmei , Lindblom Annika , Lophatananon Artitaya , Luben Robert N. , Lubiński Jan , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Mariapun Shivaani , Matsuo Keitaro , Maurer Tabea , Mavroudis Dimitrios , Meindl Alfons , Menon Usha , Milne Roger L. , Muir Kenneth , Mulligan Anna Marie , Neuhausen Susan L. , Nevanlinna Heli , Offit Kenneth , Olopade Olufunmilayo I. , Olson Janet E. , Olsson Håkan , Orr Nick , Park Sue K. , Peterlongo Paolo , Peto Julian , Plaseska-Karanfilska Dijana , Presneau Nadege , Rack Brigitte , Rau-Murthy Rohini , Rennert Gad , Rennert Hedy S. , Rhenius Valerie , Romero Atocha , Ruebner Matthias , Saloustros Emmanouil , Schmutzler Rita K. , Schneeweiss Andreas , Scott Christopher , Shah Mitul , Shen Chen-Yang , Shu Xiao-Ou , Simard Jacques , Sohn Christof , Southey Melissa C. , Spinelli John J. , Tamimi Rulla M. , Tapper William J. , Teo Soo H. , Terry Mary Beth , Torres Diana , Truong Thérèse , Untch Michael , Vachon Celine M. , van Asperen Christi J. , Wolk Alicja , Yamaji Taiki , Zheng Wei , Ziogas Argyrios , Ziv Elad , Torres-Mejía Gabriela , Dörk Thilo , Swerdlow Anthony J. , Hamann Ute , Schmidt Marjanka K. , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Hooning Maartje J. , Martens John W. M. , Hollestelle Antoinette 
Published: June 2020

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859–1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482–1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.