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

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    Authors
    Figlioli, G
    Bogliolo, M
    Catucci, I
    Caleca, L
    Lasheras, SV
    Pujol, R
    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
    Beane Freeman, LE
    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, H
    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, I
    Durda, K
    Dwek, M
    Eccles, DM
    Ekici, AB
    Eliassen, AH
    Ellberg, C
    Eriksson, M
    Evans, DG
    Fasching, PA
    Figueroa, J
    Flyger, H
    Foulkes, WD
    Friebel, TM
    Friedman, E
    Gabrielson, M
    Gaddam, P
    Gago-Dominguez, M
    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-Barrera, AM
    Haeberle, L
    Haiman, CA
    Hakansson, N
    Hall, P
    Hamann, U
    Harrington, PA
    Hein, A
    Heyworth, J
    Hillemanns, P
    Hollestelle, A
    Hopper, JL
    Hosgood, HD
    Howell, Anthony
    Hu, C
    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, I
    Koutros, S
    Kraft, P
    Lambrechts, D
    Lazaro, C
    Le, ML
    Lester, J
    Lesueur, F
    Lilyquist, J
    Loud, JT
    Lu, KH
    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, H
    Osorio, A
    Ottini, L
    Peissel, B
    Peixoto, A
    Peto, J
    Plaseska-Karanfilska, D
    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, D
    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, A
    Yang, XR
    Zheng, W
    Ziogas, A
    Zorn, KK
    Dunning, AM
    Lush, M
    Wang, Q
    McGuffog, L
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    Affiliation
    Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Bellaterra, Barcelona Spain
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    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.
    Citation
    Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, et al. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. NPJ Breast Cancer. 2019;5:38.
    Journal
    NPJ Breast Cancer
    URI
    http://hdl.handle.net/10541/622621
    DOI
    10.1038/s41523-019-0127-5
    PubMed ID
    31700994
    Additional Links
    https://dx.doi.org/10.1038/s41523-019-0127-5
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41523-019-0127-5
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