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

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MARC

Figlioli, GIFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy,IFOM - The FIRC Institute of Molecular Oncology (author)

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

Article/chapterEnglish2019

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2019-11-01
Springer Science and Business Media LLC,2019

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LIBRIS-ID:oai:prod.swepub.kib.ki.se:142209073
http://kipublications.ki.se/Default.aspx?queryparsed=id:142209073URI
https://doi.org/10.1038/s41523-019-0127-5DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-397654URI
https://lup.lub.lu.se/record/c1cc6d81-4544-45eb-b7dc-dd5e1a5e72baURI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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For complete list of authors see http://dx.doi.org/10.1038/s41523-019-0127-5
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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
arginine
arginine 658
ATM protein
BRCA1 protein
BRCA2 protein
butadiene diepoxide
checkpoint kinase 2
olaparib
partner and localizer of BRCA2
unclassified drug
Article
ATM protein gene
BRCA1 protein gene
BRCA2 protein gene
cell survival
checkpoint kinase 2 gene
chromosomal instability
chromosome fragility
controlled study
FANCM gene
female
gene
gene expression
gene mutation
genotype
human
informed consent
major clinical study
mRNA expression level
partner and localizer of BRCA2 gene
phenotype
priority journal
risk factor
sensitivity analysis
survival rate
triple negative breast cancer
Western blotting

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Bogliolo, M (author)
Catucci, I (author)
Caleca, L (author)
Lasheras, SV (author)
Pujol, R (author)
Kiiski, JI (author)
Muranen, TA (author)
Barnes, DR (author)
Dennis, J (author)
Michailidou, K (author)
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Leslie, G (author)
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Arndt, V (author)
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Czene, KKarolinska Institutet (author)
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de la Hoya, M (author)
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Diez, O (author)
Ding, YC (author)
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Flyger, H (author)
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Rickard, E (author)
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Bogwitz, M (author)
Gaff, C (author)
Lindeman, G (author)
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Scott, C (author)
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Visvader, J (author)
Taylor, J (author)
Winship, I (author)
Brennan, M (author)
Brown, M (author)
French, J (author)
Edwards, S (author)
Burgess, M (author)
Burke, J (author)
Patterson, B (author)
Butow, P (author)
Culling, B (author)
Caldon, L (author)
Callen, D (author)
Chauhan, D (author)
Eisenbruch, M (author)
Heiniger, L (author)
Chauhan, M (author)
Christian, A (author)
Dixon, J (author)
Kidd, A (author)
Cohen, P (author)
Colley, A (author)
Fenton, G (author)
Crook, A (author)
Dickson, R (author)
Field, M (author)
Cui, J (author)
Cummings, M (author)
Dawson, SJ (author)
DeFazio, A (author)
Delatycki, M (author)
Dudding, T (author)
Edkins, T (author)
Farshid, G (author)
Flanagan, J (author)
Fong, P (author)
Forrest, L (author)
Gallego-Ortega, D (author)
George, P (author)
Gill, G (author)
Kollias, J (author)
Haan, E (author)
Hart, S (author)
Jenkins, M (author)
Hunt, C (author)
Lakhani, S (author)
Lipton, L (author)
Lobb, L (author)
Mann, G (author)
McLachlan, SA (author)
O'Connell, S (author)
O'Sullivan, S (author)
Pieper, E (author)
Robinson, B (author)
Saunus, J (author)
Scott, E (author)
Shelling, A (author)
Williams, R (author)
Young, MAGenome One, Darlinghurst, NSW, Australia (author)
IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, ItalyIFOM - The FIRC Institute of Molecular Oncology (creator_code:org_t)

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By the author/editor: Figlioli, G; Bogliolo, M; Catucci, I; Caleca, L; Lasheras, SV; Pujol, R; show more...; Kiiski, JI; Muranen, TA; Barnes, DR; Dennis, J; Michailidou, K; Bolla, MK; Leslie, G; Aalfs, CM; Adank, MA; Adlard, J; Agata, S; Cadoo, K; Agnarsson, BA; Ahearn, T; Aittomaki, K; Ambrosone, CB; Andrews, L; Anton-Culver, H; Antonenkova, NN; Arndt, V; Arnold, N; Aronson, KJ; Arun, BK; Asseryanis, E; Auber, B; Auvinen, P; Azzollini, J; Balmana, J; Barkardottir, RB; Barrowdale, D; Barwell, J; Freeman, LEB; Beauparlant, CJ; Beckmann, MW; Behrens, S; Benitez, J; Berger, R; Bermisheva, M; Blanco, AM; Blomqvist, C; Bogdanova, NV; Bojesen, A; Bojesen, SE; Bonanni, B; Borg, A; Brady, AF; Brauch, H; Brenner, Hermann; Bruning, T; Burwinkel, B; Buys, SS; Caldes, T; Caliebe, A; Caligo, MA; Campa, D; Campbell, IG; Canzian, F; Castelao, JE; Chang-Claude, J; Chanock, SJ; Claes, KBM; Clarke, CL; Collavoli, A; Conner, TA; Cox, DG; Cybulski, C; Czene, K; Daly, MB; de la Hoya, M; Devilee, P; Diez, O; Ding, YC; Dite, GS; Ditsch, N; Domchek, SM; Dorfling, CM; dos-Santos-Silva ...; Durda, K; Dwek, M; Eccles, DM; Ekici, AB; Eliassen, AH; Ellberg, Carolin ...; Eriksson, M; Evans, DG; Fasching, PA; Figueroa, J; Flyger, H; Foulkes, WD; Friebel, TM; Friedman, E; Gabrielson, M; Gaddam, P; Gago-Dominguez, ...; Gao, C; Gapstur, SM; Garber, J; Garcia-Closas, M; Garcia-Saenz, JA; Gaudet, MM; Gayther, SA; Giles, GG; Glendon, G; Godwin, AK; Goldberg, MS; Goldgar, DE; Guenel, P; Gutierrez-Barrer ...; Haeberle, L; Haiman, CA; Hakansson, N; Hall, Per; Hamann, U; Harrington, PA; Hein, A; Heyworth, J; Hillemanns, P; Hollestelle, A; Hopper, JL; Hosgood, HD; Howell, A; Hu, CL; Hulick, PJ; Hunter, DJ; Imyanitov, EN; Isaacs, C; Jakimovska, M; Jakubowska, A; James, P; Janavicius, R; Janni, W; John, EM; Jones, ME; Jung, A; Kaaks, R; Karlan, BY; Khusnutdinova, E; Kitahara, CM; Konstantopoulou, ...; Koutros, S; Kraft, P; Lambrechts, D; Lazaro, C; Le Marchand, L; Lester, J; Lesueur, F; Lilyquist, J; Loud, JT; Lu, KRH; Luben, RN; Lubinski, J; Mannermaa, A; Manoochehri, M; Manoukian, S; Margolin, S; Martens, JWM; Maurer, T; Mavroudis, D; Mebirouk, N; Meindl, A; Menon, U; Miller, A; Montagna, M; Nathanson, KL; Neuhausen, SL; Newman, WG; Nguyen-Dumont, T; Nielsen, FC; Nielsen, S; Nikitina-Zake, L; Offit, K; Olah, E; Olopade, OI; Olshan, AF; Olson, JE; Olsson, Håkan; Osorio, A; Ottini, L; Peissel, B; Peixoto, A; Peto, J; Plaseska-Karanfi ...; Pocza, T; Presneau, N; Pujana, MA; Punie, K; Rack, B; Rantala, J; Rashid, MU; Rau-Murthy, R; Rennert, G; Lejbkowicz, F; Rhenius, V; Romero, A; Rookus, MA; Ross, EA; Rossing, M; Rudaitis, V; Ruebner, M; Saloustros, E; Sanden, K; Santamarina, M; Scheuner, MT; Schmutzler, RK; Schneider, M; Scott, C; Senter, L; Shah, M; Sharma, P; Shu, XO; Simard, J; Singer, CF; Sohn, C; Soucy, P; Southey, MC; Spinelli, JJ; Steele, L; Stoppa-Lyonnet, ...; Tapper, WJ; Teixeira, MR; Terry, MB; Thomassen, M; Thompson, J; Thull, DL; Tischkowitz, M; Tollenaar, RAEM; Torres, D; Troester, MA; Truong, T; Tung, N; Untch, M; Vachon, CM; van Rensburg, EJ; van Veen, EM; Vega, A; Viel, A; Wappenschmidt, B; Weitzel, JN; Wendt, C; Wieme, G; Wolk, Alicja; Yang, XHR; Zheng, W; Ziogas, A; Zorn, KK; Dunning, AM; Lush, M; Wang, Q; McGuffog, L; Parsons, MT; Pharoah, PDP; Fostira, F; Toland, AE; Andrulis, IL; Ramus, SJ; Swerdlow, AJ; Greene, MH; Chung, WK; Milne, RL; Chenevix-Trench, ...; Dork, T; Schmidt, MK; Easton, DF; Radice, P; Hahnen, E; Antoniou, AC; Couch, FJ; Nevanlinna, H; Surralles, J; Peterlongo, P; Balleine, R; Baxter, R; Braye, S; Carpenter, J; Dahlstrom, J; Forbes, J; Lee, CS; Marsh, D; Morey, A; Pathmanathan, N; Scott, R; Simpson, P; Spigelman, A; Wilcken, N; Yip, D; Zeps, N; Belotti, M; Bertrand, O; Birot, AM; Buecher, B; Caputo, S; Dupre, A; Fourme, E; Gauthier-Villars ...; Golmard, L; Le Mentec, M; Moncoutier, V; de Pauw, A; Saule, C; Boutry-Kryza, N; Calender, A; Giraud, S; Leone, M; Bressac-de-Paill ...; Caron, O; Guillaud-Bataill ...; Bignon, YJ; Uhrhammer, N; Bonadona, V; 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