The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Gisella Figlioli , Massimo Bogliolo (1) , Irene Catucci (2) , Laura Caleca , Sandra Viz Lasheras , Roser Pujol (3) , Johanna Kiiski , Taru Muranen (4) , Daniel Barnes , Joe Dennis , Kyriaki Michailidou , Manjeet Bolla , Goska Leslie , Cora Aalfs (5) , Muriel Adank , Julian Adlard (6) , Simona Agata , Karen Cadoo , Bjarni Agnarsson (7) , Thomas Ahearn , Kristiina Aittomäki (8) , Christine Ambrosone , Lesley Andrews , Hoda Anton-Culver , Natalia Antonenkova , Volker Arndt , Norbert Arnold (9) , Kristan Aronson , Banu Arun , Ella Asseryanis , Bernd Auber , Päivi Auvinen , Jacopo Azzollini (10) , Judith Balmaña (11) , Rosa Barkardottir (12) , Daniel Barrowdale (13) , Julian Barwell (14) , Laura E Beane Freeman (15) , Charles Joly Beauparlant , Matthias Beckmann , Sabine Behrens (16) , Javier Benitez (17) , Raanan Berger (18) , Marina Bermisheva (19) , Amie Blanco , Carl Blomqvist (20) , Natalia Bogdanova (21) , Anders Bojesen , Stig Bojesen , Bernardo Bonanni (22) , Åke Borg (23) , Angela F. Brady (24) , Hiltrud Brauch (25) , Hermann Brenner (26) , Thomas Brüning (27) , Barbara Burwinkel (28) , Saundra Buys (29) , Trinidad Caldés (30) , Almuth Caliebe , Maria Adelaide Caligo (31) , Daniele Campa (32) , Ian Campbell , Federico Canzian (33) , Jose Castelao , Jenny Chang-Claude (34) , Stephen Chanock (35) , Kathleen Claes , Christine Clarke , Anita Collavoli , Thomas Conner , David G Cox (36) , Cezary Cybulski (37) , Kamila Czene (38) , Mary B. Daly (39) , Miguel de La Hoya (30) , Peter Devilee (40) , Orland Diez (41) , Yuan Chun Ding , Gillian Dite , Nina Ditsch (42) , Susan Domchek (43) , Cecilia Dorfling , Isabel Dos-Santos-Silva , Katarzyna Durda (37) , Miriam Dwek , Diana Eccles (44) , Arif Ekici , A. Heather Eliassen , Carolina Ellberg , Mikael Eriksson (45) , D. Gareth Evans (46) , Peter Fasching , Jonine Figueroa , Henrik Flyger (47) , William Foulkes (48) , Tara Friebel , Eitan Friedman (49) , Marike Gabrielson , Pragna Gaddam , Manuela Gago-Dominguez , Chi Gao , Susan Gapstur , Judy Garber , Montserrat García-Closas (50) , José García-Sáenz , Mia Gaudet (51) , Simon Gayther (52) , Graham G Giles (53) , Gord Glendon (54) , Andrew Godwin (55) , Mark S. Goldberg (56) , David E. Goldgar (57) , Pascal Guénel (58) , Angelica Gutierrez-Barrera , Lothar Haeberle (59) , Christopher Haiman (60) , Niclas Håkansson , Per Hall (38) , Ute Hamann (61) , Patricia Harrington (62) , Alexander Hein (59) , Jane Heyworth , Peter Hillemanns , Antoinette Hollestelle (63) , John Hopper (64) , H. Dean Hosgood , Anthony Howell (65) , Chunling Hu , Peter Hulick , David R. Hunter (66) , Evgeny Imyanitov (67) , Claudine Isaacs (68) , Milena Jakimovska , Anna Jakubowska (37) , Paul James , Ramunas Janavicius (69) , Wolfgang Janni (70) , Esther M. John (71) , Michael Jones , Audrey Jung , Rudolf Kaaks (72) , Beth Karlan (73) , Elza K. Khusnutdinova (74) , Cari Kitahara (50) , Irene Konstantopoulou (75) , Stella Koutros (15) , Peter Kraft (76) , Diether Lambrechts (77) , Conxi Lázaro (78) , Loïc Le Marchand (79) , Jenny Lester , Fabienne Lesueur (80) , Jenna Lilyquist , Jennifer Loud (81) , Karen Lu , Robert Luben (82) , Jan Lubinski (37) , Arto Mannermaa , Mehdi Manoochehri , Siranoush Manoukian (83) , Sara Margolin , John Martens , Tabea Maurer , Dimitrios Mavroudis , Noura Mebirouk (80) , Alfons Meindl (84) , Usha Menon (85) , Austin Miller , Marco Montagna (86) , Katherine Nathanson (87) , Susan Neuhausen (88) , William Newman , Tú Nguyen-Dumont (89) , Finn Cilius Nielsen , Sarah Nielsen , Liene Nikitina-Zake , Kenneth Offit (90) , Edith Olah (91) , Olufunmilayo Olopade (92) , Andrew F. Olshan (93) , Janet Olson , Håkan Olsson (45) , Ana Osorio (94) , Laura Ottini (95) , Bernard Peissel (83) , Ana Peixoto (96) , Julian Peto (97) , Dijana Plaseska-Karanfilska , Timea Pocza , Nadege Presneau , Miquel Angel Pujana , Kevin Punie , Brigitte Rack (98) , Johanna Rantala (99) , Muhammad Rashid (100) , Rohini Rau-Murthy , Gad Rennert (101) , Flavio Lejbkowicz (101) , Valerie Rhenius , Atocha Romero , Matti A. Rookus (102) , Eric Ross , Maria Rossing (103) , Vilius Rudaitis , Matthias Ruebner , Emmanouil Saloustros , Kristin Sanden , Marta Santamariña , Maren Scheuner , Rita Schmutzler (104) , Michael Schneider , Christopher Scott (105) , Leigha Senter , Mitul Shah , Priyanka Sharma , Xiao-Ou Shu (106) , Jacques Simard (107) , Christian Singer (108) , Christof Sohn (109) , Penny Soucy (110) , Melissa Southey (111) , John Spinelli , Linda Steele , Dominique Stoppa-Lyonnet (112) , William Tapper , Manuel R Teixeira (113) , Mary Beth Terry (114) , Mads Thomassen (115) , Jennifer Thompson , Darcy Thull , Marc Tischkowitz (96) , Rob A.E.M. Tollenaar , Diana Torres (116) , Melissa Troester , Thérèse Truong (58) , Nadine Tung , Michael Untch (117) , Celine Vachon , Elizabeth Jansen van Rensburg (118) , Elke van Veen , Ana Vega (119) , Alessandra Viel (120) , Barbara Wappenschmidt (121) , Jeffrey Weitzel (122) , Camilla Wendt , Greet Wieme , Alicja Wolk (123) , Xiaohong Yang , Wei Zheng (124) , Argyrios Ziogas , Kristin Zorn , Alison Dunning (125) , Michael Lush (126) , Qin Wang (127) , Lesley Mcguffog (128) , Michael Parsons (129) , Paul Pharoah (130) , Florentia Fostira , Amanda Toland (131) , Irene Andrulis (132) , Susan Ramus (133) , Anthony Swerdlow (134) , Mark Greene (81) , Wendy Chung (135) , Roger L Milne (136) , Georgia Chenevix-Trench (137) , Thilo Dörk (21) , Marjanka Schmidt , Douglas F. Easton (138) , Paolo Radice (139) , Eric Hahnen , Antonis C. Antoniou (138) , Fergus Couch (140) , Heli Nevanlinna (141) , Jordi Surrallés (1) , Paolo Peterlongo (142)

1 Department of Genetics and Microbiology
2 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
3 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
4 Department of Obstetrics and Gynecology
5 Department of Clinical Genetics
6 Yorkshire Regional Genetics Service
7 Department of Pathology
8 Department of Clinical Genetics
9 Division of Oncology, Department of Gynaecology and Obstetrics
10 UNIMI - Università degli Studi di Milano = University of Milan
11 Medical Oncology Department
12 Department of Pathology
13 Centre for Cancer Genetic Epidemiology
14 Leicestershire Clinical Genetics Service
15 Occupational and Environmental Epidemiology Branch [Bethesda, Maryland]
16 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
17 Departemento Genetica Humana
18 Chaim Sheba Medical Center
19 Institute of Biochemistry and Genetics of Ufa Scientific Centre
20 Department of Oncology
21 MHH - Department of Obstetrics and Gynaecology
22 Division of Cancer Prevention and Genetics
23 Department of Oncology, Clinical Sciences
24 North West Thames Regional Genetics
25 Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology [Stuttgart]
26 Division of Clinical Epidemiology and Aging Research
27 IPA - Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
28 Molecular Epidemiology Research Group
29 Department of Internal Medicine
30 Molecular Oncology Laboratory
31 Section of Genetic Oncology
32 University of Pisa - Università di Pisa
33 Department of Cancer Epidemiology
34 Division of Cancer Epidemiology
35 Division of Cancer Epidemiology and Genetics
36 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
37 Department of Genetics and Pathology
38 MEB - Department of Medical Epidemiology and Biostatistics
39 Division of Population Science
40 Department of Human Genetics & Department of Pathology
41 Oncogenetics Laboratory
42 Department of Obstetrics and Gynecology [Munich, Germany]
43 Abramson Cancer Center
44 Wessex clinical genetics service
45 Department of Oncology
46 Department of Genomic Medicine
47 Department of Breast Surgery
48 Department of Human Genetics [Montréal]
49 The Susanne Levy Gertner Oncogenetics Unit
50 NCI-NIH - National Cancer Institute [Bethesda]
51 Epidemiology Research Program
52 Department of Preventive Medicine
53 University of Melbourne
54 Ontario Cancer Genetics Network
55 Department of Pathology and Laboratory Medicine
56 McGill University = Université McGill [Montréal, Canada]
57 IACR - International Agency for Cancer Research
58 CESP - Centre de recherche en épidémiologie et santé des populations
59 Department of OB/Gyn, University Breast Center Franconia
60 USC - University of Southern California
61 Molecular Genetics of Breast Cancer
62 Centre for Cancer Genetic Epidemiology [Cambridge]
63 Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center
64 Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia
65 The Christie
66 Department of Statistics, Penn State University
67 Laboratory of Molecular Oncology
68 Lombardi Comprehensive Cancer Center
69 Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion
70 Department of Gynaecology and Obstetrics
71 Department of Epidemiology
72 Unit of Nutrition and Cancer
73 Women's Cancer Program
74 Institute of Biochemistry and Genetics [Bashkortostan Republic, Russia]
75 NCSR - National Center for Scientific Research "Demokritos"
76 Department of Epidemiology
77 Laboratory for translational genetics Leuven
78 Genetic Counseling and Hereditary Cancer Programme
79 UHM - University of Hawai‘i [Mānoa]
80 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
81 Clinical Genetics Branch
82 Strangeways Research Laboratory
83 Unit of Medical Genetics
84 Department of Gynaecology and Obstetrics
85 Institute for Women's Health [London]
86 Immunology and Molecular Oncology Unit
87 Department of Medicine, Medical Genetics
88 Department of Population Sciences
89 Section Génétique - Groupe Prédispositions génétiques au cancer
90 Clinical Genetics Service
91 Department of Molecular Genetics and Department of Chemotherapy
92 University of Chicago
93 Recherches épidémiologiques et statistiques sur l'environnement et la santé.
94 Human Genetics Group
95 Department of Molecular Medicine
96 Department of Genetics
97 Non-Communicable Disease Epidemiology Unit
98 Department of Gynecology and Obstetrics
99 Department of Clinical Genetics
100 Umm Al-Qura University
101 Department of Community Medicine and Epidemiology
102 Department of Epidemiology
103 ITU - IT University of Copenhagen
104 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un
105 QUB - Queen's University [Belfast]
106 Vanderbilt Epidemiology Center, Institute for Medicine and Public Health
107 Laboratoire de Génomique des Cancers
108 Division of Special Gynecology
109 Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics
110 Cancer Genomics Laboratory
111 Department of Pathology
112 U830 - Unité de génétique et biologie des cancers
113 ICBAS - Instituto de Ciências Biomédicas de Abel Salazar
114 Department of Epidemiology [Columbia University]
115 Department of Clinical Genetics
116 Instituto de Genética Humana
117 Department of Gynecology and Obstetrics
118 Cancer Genetics Laboratory
119 Genomic Medicine Group
120 CRO - Centro di Riferimento Oncologico
121 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics,
122 City of Hope Comprehensive Cancer Center and Department of Population Sciences
123 Karolinska Institutet [Stockholm]
124 CAS - Center for Astrophysical Sciences [Baltimore]
125 CAM - University of Cambridge [UK]
126 EMBL-EBI - European Bioinformatics Institute [Hinxton]
127 USTB - University of Science and Technology Beijing [Beijing]
128 Strangeways Research Laboratory
129 UPPA - Université de Pau et des Pays de l'Adour
130 Department of Oncology
131 Department of Molecular Virology, Immunology and Medical Genetics [Colombus]
132 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology
133 Department of Preventive Medicine
134 The institute of cancer research [London]
135 Department of Medical Genetics
136 Cancer Epidemiology Centre
137 Queensland Institute of Medical Research
138 Cancer Research U.K. Genetic Epidemiology Unit
139 Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medici
140 Department of Laboratory Medicine and Pathology
141 Department of Obstetrics and Gynecology
142 Unit of Molecular Bases of Genetic Risk and Genetic Testing

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.

Domaines: Bactériologie; Cardiologie et système cardiovasculaire; Maladies émergentes; Maladies infectieuses; Parasitologie; Virologie

Gisella Figlioli, Massimo Bogliolo, Irene Catucci, Laura Caleca, Sandra Viz Lasheras, et al.. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. npj Breast Cancer, 2019, 5 (1), ⟨10.1038/s41523-019-0127-5⟩. ⟨hal-02463255⟩