The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Authors: Figlioli Gisella , Bogliolo Massimo , Catucci Irene , Caleca Laura , Lasheras Sandra Viz , Pujol Roser , Kiiski Johanna I. , Muranen Taru A. , Barnes Daniel R. , Dennis Joe , Michailidou Kyriaki , Bolla Manjeet K. , Leslie Goska , Aalfs Cora M. ,   ABCTB Investigators, Balleine Rosemary , Baxter Robert , Braye Stephen , Carpenter Jane , Dahlstrom Jane , Forbes John , Lee C. Soon , Marsh Deborah , Morey Adrienne , Pathmanathan Nirmala , Scott Rodney , Simpson Peter , Spigelman Allan , Wilcken Nicholas , Yip Desmond , Zeps Nikolajs , Adank Muriel A. , Adlard Julian , Agata Simona , Cadoo Karen , Agnarsson Bjarni A. , Ahearn Thomas , Aittomäki Kristiina , Ambrosone Christine B. , Andrews Lesley , Anton-Culver Hoda , Antonenkova Natalia N. , Arndt Volker , Arnold Norbert , Aronson Kristan J. , Arun Banu K. , Asseryanis Ella , Auber Bernd , Auvinen Päivi , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B. , Barrowdale Daniel , Barwell Julian , Beane Freeman Laura E. , Beauparlant Charles Joly , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Berger Raanan , Bermisheva Marina , Blanco Amie M. , Blomqvist Carl , Bogdanova Natalia V. , Bojesen Anders , Bojesen Stig E. , Bonanni Bernardo , Borg Ake , Brady Angela F. , Brauch Hiltrud , Brenner Hermann , Brüning Thomas , Burwinkel Barbara , Buys Saundra S. , Caldés Trinidad , Caliebe Almuth , Caligo Maria A. , Campa Daniele , Campbell Ian G. , Canzian Federico , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Claes Kathleen B. M. , Clarke Christine L. , Collavoli Anita , Conner Thomas A. , Cox David G. , Cybulski Cezary , Czene Kamila , Daly Mary B. , de la Hoya Miguel , Devilee Peter , Diez Orland , Ding Yuan Chun , Dite Gillian S. , Ditsch Nina , Domchek Susan M. , Dorfling Cecilia M. , dos-Santos-Silva Isabel , Durda Katarzyna , Dwek Miriam , Eccles Diana M. , Ekici Arif B. , Eliassen A. Heather , Ellberg Carolina , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine , Flyger Henrik , Foulkes William D. , Friebel Tara M. , Friedman Eitan , Gabrielson Marike , Gaddam Pragna , Gago-Dominguez Manuela , Gao Chi , Gapstur Susan M. , Garber Judy , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Gayther Simon A. ,   GEMO Study Collaborators, Belotti Muriel , Bertrand Ophélie , Birot Anne-Marie , Buecher Bruno , Caputo Sandrine , Dupré Anaïs , Fourme Emmanuelle , Gauthier-Villars Marion , Golmard Lisa , Le Mentec Marine , Moncoutier Virginie , de Pauw Antoine , Saule Claire , Boutry-Kryza Nadia , Calender Alain , Giraud Sophie , Léone Mélanie , Bressac-de-Paillerets Brigitte , Caron Olivier , Guillaud-Bataille Marine , Bignon Yves-Jean , Uhrhammer Nancy , Bonadona Valérie , Lasset Christine , Berthet Pascaline , Castera Laurent , Vaur Dominique , Bourdon Violaine , Noguès Catherine , Noguchi Tetsuro , Popovici Cornel , Remenieras Audrey , Sobol Hagay , Coupier Isabelle , Pujol Pascal , Adenis Claude , Dumont Aurélie , Révillion Françoise , Muller Danièle , Barouk-Simonet Emmanuelle , Bonnet Françoise , Bubien Virginie , Longy Michel , Sevenet Nicolas , Gladieff Laurence , Guimbaud Rosine , Feillel Viviane , Toulas Christine , Dreyfus Hélène , Leroux Christine Dominique , Peysselon Magalie , Rebischung Christine , Legrand Clémentine , Baurand Amandine , Bertolone Geoffrey , Coron Fanny , Faivre Laurence , Jacquot Caroline , Lizard Sarab , Kientz Caroline , Lebrun Marine , Prieur Fabienne , Fert-Ferrer Sandra , Mari Véronique , Vénat-Bouvet Laurence , Bézieau Stéphane , Delnatte Capucine , Mortemousque Isabelle , Colas Chrystelle , Coulet Florence , Soubrier Florent , Warcoin Mathilde , Bronner Myriam , Sokolowska Johanna , Collonge-Rame Marie-Agnès , Damette Alexandre , Gesta Paul , Lallaoui Hakima , Chiesa Jean , Molina-Gomes Denise , Ingster Olivier , Manouvrier-Hanu Sylvie , Lejeune Sophie , Giles Graham G. , Glendon Gord , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , Guénel Pascal , Gutierrez-Barrera Angelica M. , Haeberle Lothar , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Harrington Patricia A. , Hein Alexander , Heyworth Jane , Hillemanns Peter , Hollestelle Antoinette , Hopper John L. , Hosgood H. Dean , Howell Anthony , Hu Chunling , Hulick Peter J. , Hunter David J. , Imyanitov Evgeny N. ,   KConFab, Aghmesheh Morteza , Greening Sian , Amor David , Gattas Mike , Botes Leon , Buckley Michael , Friedlander Michael , Koehler Jessica , Meiser Bettina , Saleh Mona , Salisbury Elizabeth , Trainer Alison , Tucker Kathy , Antill Yoland , Dobrovic Alexander , Fellows Andrew , Fox Stephen , Harris Marion , Nightingale Sophie , Phillips Kelly , Sambrook Joe , Thorne Heather , Armitage Shane , Arnold Leanne , Balleine Rosemary , Kefford Rick , Kirk Judy , Rickard Edwina , Bastick Patti , Beesley Jonathan , Hayward Nick , Spurdle Amanda , Walker Logan , Beilby John , Saunders Christobel , Bennett Ian , Blackburn Anneke , Bogwitz Michael , Gaff Clara , Lindeman Geoff , Pachter Nick , Scott Clare , Sexton Adrienne , Visvader Jane , Taylor Jessica , Winship Ingrid , Brennan Meagan , Brown Melissa , French Juliet , Edwards Stacey , Burgess Matthew , Burke Jo , Patterson Briony , Butow Phyllis , Culling Bronwyn , Caldon Liz , Callen David , Chauhan Deepa , Eisenbruch Maurice , Heiniger Louise , Chauhan Manisha , Christian Alice , Dixon Joanne , Kidd Alexa , Cohen Paul , Colley Alison , Fenton Georgina , Crook Ashley , Dickson Rebecca , Field Michael , Marsh Deborah , Cui James , Cummings Margaret , Dawson Sarah-Jane , DeFazio Anna , Delatycki Martin , Dudding Tracy , Edkins Ted , Farshid Gelareh , Flanagan James , Fong Peter , Forrest Laura , Gallego-Ortega David , George Peter , Gill Grantley , Kollias James , Haan Eric , Hart Stewart , Jenkins Mark , Hunt Clare , Lakhani Sunil , Lipton Lara , Lobb Liz , Mann Graham , McLachlan Sue Anne , O’Connell Shona , O’Sullivan Sarah , Pieper Ellen , Robinson Bridget , Saunus Jodi , Scott Elizabeth , Scott Rodney , Shelling Andrew , Simpson Peter , Williams Rachael , Young Mary Ann , Isaacs Claudine , Jakimovska Milena , Jakubowska Anna , James Paul , Janavicius Ramunas , Janni Wolfgang , John Esther M. , Jones Michael E. , Jung Audrey , Kaaks Rudolf , Karlan Beth Y. , Khusnutdinova Elza , Kitahara Cari M. , Konstantopoulou Irene , Koutros Stella , Kraft Peter , Lambrechts Diether , Lazaro Conxi , Le Marchand Loic , Lester Jenny , Lesueur Fabienne , Lilyquist Jenna , Loud Jennifer T. , Lu Karen H. , Luben Robert N. , Lubinski Jan , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martens John W. M. , Maurer Tabea , Mavroudis Dimitrios , Mebirouk Noura , Meindl Alfons , Menon Usha , Miller Austin , Montagna Marco , Nathanson Katherine L. , Neuhausen Susan L. , Newman William G. , Nguyen-Dumont Tu , Nielsen Finn Cilius , Nielsen Sarah , Nikitina-Zake Liene , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olshan Andrew F. , Olson Janet E. , Olsson Håkan , Osorio Ana , Ottini Laura , Peissel Bernard , Peixoto Ana , Peto Julian , Plaseska-Karanfilska Dijana , Pocza Timea , Presneau Nadege , Pujana Miquel Angel , Punie Kevin , Rack Brigitte , Rantala Johanna , Rashid Muhammad U. , Rau-Murthy Rohini , Rennert Gad , Lejbkowicz Flavio , Rhenius Valerie , Romero Atocha , Rookus Matti A. , Ross Eric A. , Rossing Maria , Rudaitis Vilius , Ruebner Matthias , Saloustros Emmanouil , Sanden Kristin , Santamariña Marta , Scheuner Maren T. , Schmutzler Rita K. , Schneider Michael , Scott Christopher , Senter Leigha , Shah Mitul , Sharma Priyanka , Shu Xiao-Ou , Simard Jacques , Singer Christian F. , Sohn Christof , Soucy Penny , Southey Melissa C. , Spinelli John J. , Steele Linda , Stoppa-Lyonnet Dominique , Tapper William J. , Teixeira Manuel R. , Terry Mary Beth , Thomassen Mads , Thompson Jennifer , Thull Darcy L. , Tischkowitz Marc , Tollenaar Rob A.E.M. , Torres Diana , Troester Melissa A. , Truong Thérèse , Tung Nadine , Untch Michael , Vachon Celine M. , van Rensburg Elizabeth J. , van Veen Elke M. , Vega Ana , Viel Alessandra , Wappenschmidt Barbara , Weitzel Jeffrey N. , Wendt Camilla , Wieme Greet , Wolk Alicja , Yang Xiaohong R. , Zheng Wei , Ziogas Argyrios , Zorn Kristin K. , Dunning Alison M. , Lush Michael , Wang Qin , McGuffog Lesley , Parsons Michael T. , Pharoah Paul D. P. , Fostira Florentia , Toland Amanda E. , Andrulis Irene L. , Ramus Susan J. , Swerdlow Anthony J. , Greene Mark H. , Chung Wendy K. , Milne Roger L. , Chenevix-Trench Georgia , Dörk Thilo , Schmidt Marjanka K. , Easton Douglas F. , Radice Paolo , Hahnen Eric , Antoniou Antonis C. , Couch Fergus J. , Nevanlinna Heli , Surrallés Jordi , Peterlongo Paolo 
Published: November 2019

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.