Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus
Authors: Lawrenson Kate , Kar Siddhartha , McCue Karen , Kuchenbaeker Karoline , Michailidou Kyriaki , Tyrer Jonathan , Beesley Jonathan , Ramus Susan J. , Li Qiyuan , Delgado Melissa K. , Lee Janet M. , Aittomäki Kristiina , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Arun Banu K. , Arver Brita , Bandera Elisa V. , Barile Monica , Barkardottir Rosa B. , Barrowdale Daniel , Beckmann Matthias W. , Benitez Javier , Berchuck Andrew , Bisogna Maria , Bjorge Line , Blomqvist Carl , Blot William , Bogdanova Natalia , Bojesen Anders , Bojesen Stig E. , Bolla Manjeet K. , Bonanni Bernardo , Børresen-Dale Anne-Lise , Brauch Hiltrud , Brennan Paul , Brenner Hermann , Bruinsma Fiona , Brunet Joan , Buhari Shaik Ahmad , Burwinkel Barbara , Butzow Ralf , Buys Saundra S. , Cai Qiuyin , Caldes Trinidad , Campbell Ian , Canniotto Rikki , Chang-Claude Jenny , Chiquette Jocelyne , Choi Ji-Yeob , Claes Kathleen B. M. ,   GEMO Study Collaborators, Collonge-Rame Marie- Agnès , Damette Alexandre , Barouk-Simonet Emmanuelle , Bonnet Françoise , Bubien Virginie , Sevenet Nicolas , Longy Michel , Berthet Pascaline , Vaur Dominique , Castera Laurent , Ferrer Sandra Fert , Bignon Yves-Jean , Uhrhammer Nancy , Coron Fanny , Faivre Laurence , Baurand Amandine , Jacquot Caroline , Bertolone Geoffrey , Lizard Sarab , Leroux Dominique , Dreyfus Hélène , Rebischung Christine , Peysselon Magalie , Peyrat Jean-Philippe , Fournier Joëlle , Révillion Françoise , Adenis Claude , Vénat-Bouvet Laurence , Léone Mélanie , Boutry-Kryza Nadia , Calender Alain , Giraud Sophie , Verny-Pierre Carole , Lasset Christine , Bonadona Valérie , Barjhoux Laure , Sobol Hagay , Bourdon Violaine , Noguchi Tetsuro , Remenieras Audrey , Coupier Isabelle , Pujol Pascal , Sokolowska Johanna , Bronner Myriam , Delnatte Capucine , Bézieau Stéphane , Mari Véronique , Gauthier-Villars Marion , Buecher Bruno , Rouleau Etienne , Golmard Lisa , Moncoutier Virginie , Belotti Muriel , de Pauw Antoine , Elan Camille , Fourme Emmanuelle , Birot Anne-Marie , Saule Claire , Laurent Maïté , Houdayer Claude , Lesueur Fabienne , Mebirouk Noura , Coulet Florence , Colas Chrystelle , Soubrier Florent , Warcoin Mathilde , Prieur Fabienne , Lebrun Marine , Kientz Caroline , Muller Danièle , Fricker Jean-Pierre , Toulas Christine , Guimbaud Rosine , Gladieff Laurence , Feillel Viviane , Mortemousque Isabelle , Bressac-de-Paillerets Brigitte , Caron Olivier , Guillaud-Bataille Marine , Cook Linda S. , Cox Angela , Cramer Daniel W. , Cross Simon S. , Cybulski Cezary , Czene Kamila , Daly Mary B. , Damiola Francesca , Dansonka-Mieszkowska Agnieszka , Darabi Hatef , Dennis Joe , Devilee Peter , Diez Orland , Doherty Jennifer A. , Domchek Susan M. , Dorfling Cecilia M. , Dörk Thilo , Dumont Martine , Ehrencrona Hans , Ejlertsen Bent , Ellis Steve ,   EMBRACE, Gregory Helen , Miedzybrodzka Zosia , Morrison Patrick J. , Donaldson Alan , Rogers Mark T. , Kennedy M. John , Porteous Mary E. , Brady Angela , Barwell Julian , Foo Claire , Lalloo Fiona , Side Lucy E. , Eason Jacqueline , Henderson Alex , Walker Lisa , Cook Jackie , Snape Katie , Murray Alex , McCann Emma , Engel Christoph , Lee Eunjung , Evans D. Gareth , Fasching Peter A. , Feliubadalo Lidia , Figueroa Jonine , Flesch-Janys Dieter , Fletcher Olivia , Flyger Henrik , Foretova Lenka , Fostira Florentia , Foulkes William D. , Fridley Brooke L. , Friedman Eitan , Frost Debra , Gambino Gaetana , Ganz Patricia A. , Garber Judy , García-Closas Montserrat , Gentry-Maharaj Aleksandra , Ghoussaini Maya , Giles Graham G. , Glasspool Rosalind , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Goode Ellen L. , Goodman Marc T. , Greene Mark H. , Gronwald Jacek , Guénel Pascal , Haiman Christopher A. , Hall Per , Hallberg Emily , Hamann Ute , Hansen Thomas V. O. , Harrington Patricia A. , Hartman Mikael , Hassan Norhashimah , Healey Sue ,   The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Rookus M. A. , van Leeuwen F. E. , van der Kolk L. E. , Schmidt M. K. , Russell N. S. , de Lange J. L. , Wijnands R. , Collée J. M. , Hooning M. J. , Seynaeve C. , van Deurzen C. H. M. , Obdeijn I. M. , van Asperen C. J. , Tollenaar R. A. E. M. , van Cronenburg T. C. T. E. F. , Kets C. M. , Ausems M. G. E. M. , van der Pol C. C. , van Os T. A. M. , Waisfisz Q. , Meijers-Heijboer H. E. J. , Gómez-Garcia E. B. , Oosterwijk J. C. , Mourits M. J. , de Bock G. H. , Vasen H. F. , Siesling S. , Verloop J. , Overbeek L. I. H. , Heitz Florian , Herzog Josef , Høgdall Estrid , Høgdall Claus K. , Hogervorst Frans B. L. , Hollestelle Antoinette , Hopper John L. , Hulick Peter J. , Huzarski Tomasz , Imyanitov Evgeny N. ,   KConFab Investigators, Fox Stephen , Kirk Judy , Lindeman Geoff , Price Melanie ,   Australian Ovarian Cancer Study Group, Bowtell David , deFazio Anna , Webb Penny , Isaacs Claudine , Ito Hidemi , Jakubowska Anna , Janavicius Ramunas , Jensen Allan , John Esther M. , Johnson Nichola , Kabisch Maria , Kang Daehee , Kapuscinski Miroslav , Karlan Beth Y. , Khan Sofia , Kiemeney Lambertus A. , Kjaer Susanne Kruger , Knight Julia A. , Konstantopoulou Irene , Kosma Veli-Matti , Kristensen Vessela , Kupryjanczyk Jolanta , Kwong Ava , de la Hoya Miguel , Laitman Yael , Lambrechts Diether , Le Nhu , De Leeneer Kim , Lester Jenny , Levine Douglas A. , Li Jingmei , Lindblom Annika , Long Jirong , Lophatananon Artitaya , Loud Jennifer T. , Lu Karen , Lubinski Jan , Mannermaa Arto , Manoukian Siranoush , Le Marchand Loic , Margolin Sara , Marme Frederik , Massuger Leon F. A. G. , Matsuo Keitaro , Mazoyer Sylvie , McGuffog Lesley , McLean Catriona , McNeish Iain , Meindl Alfons , Menon Usha , Mensenkamp Arjen R. , Milne Roger L. , Montagna Marco , Moysich Kirsten B. , Muir Kenneth , Mulligan Anna Marie , Nathanson Katherine L. , Ness Roberta B. , Neuhausen Susan L. , Nevanlinna Heli , Nord Silje , Nussbaum Robert L. , Odunsi Kunle , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olson Janet E. , Olswold Curtis , O’Malley David , Orlow Irene , Orr Nick , Osorio Ana , Park Sue Kyung , Pearce Celeste L. , Pejovic Tanja , Peterlongo Paolo , Pfeiler Georg , Phelan Catherine M. , Poole Elizabeth M. , Pylkäs Katri , Radice Paolo , Rantala Johanna , Rashid Muhammad Usman , Rennert Gad , Rhenius Valerie , Rhiem Kerstin , Risch Harvey A. , Rodriguez Gus , Rossing Mary Anne , Rudolph Anja , Salvesen Helga B. , Sangrajrang Suleeporn , Sawyer Elinor J. , Schildkraut Joellen M. , Schmidt Marjanka K. , Schmutzler Rita K. , Sellers Thomas A. , Seynaeve Caroline , Shah Mitul , Shen Chen-Yang , Shu Xiao-Ou , Sieh Weiva , Singer Christian F. , Sinilnikova Olga M. , Slager Susan , Song Honglin , Soucy Penny , Southey Melissa C. , Stenmark-Askmalm Marie , Stoppa-Lyonnet Dominique , Sutter Christian , Swerdlow Anthony , Tchatchou Sandrine , Teixeira Manuel R. , Teo Soo H. , Terry Kathryn L. , Terry Mary Beth , Thomassen Mads , Tibiletti Maria Grazia , Tihomirova Laima , Tognazzo Silvia , Toland Amanda Ewart , Tomlinson Ian , Torres Diana , Truong Thérèse , Tseng Chiu-chen , Tung Nadine , Tworoger Shelley S. , Vachon Celine , van den Ouweland Ans M. W. , van Doorn Helena C. , van Rensburg Elizabeth J. , Van't Veer Laura J. , Vanderstichele Adriaan , Vergote Ignace , Vijai Joseph , Wang Qin , Wang-Gohrke Shan , Weitzel Jeffrey N. , Wentzensen Nicolas , Whittemore Alice S. , Wildiers Hans , Winqvist Robert , Wu Anna H. , Yannoukakos Drakoulis , Yoon Sook-Yee , Yu Jyh-Cherng , Zheng Wei , Zheng Ying , Khanna Kum Kum , Simard Jacques , Monteiro Alvaro N. , French Juliet D. , Couch Fergus J. , Freedman Matthew L. , Easton Douglas F. , Dunning Alison M. , Pharoah Paul D. , Edwards Stacey L. , Chenevix-Trench Georgia , Antoniou Antonis C. , Gayther Simon A. 
Published: September 2016

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.