Melbourne School of Population and Global Health - Research Publications

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    The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
    Figlioli, G ; Bogliolo, M ; Catucci, I ; Caleca, L ; Viz Lasheras, S ; Pujol, R ; Kiiski, J ; 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, N ; Bojesen, A ; Bojesen, SE ; Bonanni, B ; Borg, A ; Brady, AF ; Brauch, H ; Brenner, H ; Bruening, 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, A ; 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 Marchand, L ; 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, O ; Olshan, AF ; Olson, JE ; Olsson, H ; Osorio, A ; Ottini, L ; Peissel, B ; Peixoto, A ; Peto, J ; Plaseska-Karanfilska, D ; Pocza, T ; Presneau, N ; Angel Pujana, M ; 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, X-O ; 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 ; Parsons, MT ; Pharoah, PDP ; Fostira, F ; Toland, AE ; Andrulis, IL ; Ramus, SJ ; Swerdlow, AJ ; Greene, MH ; Chung, WK ; Milne, RL ; Chenevix-Trench, G ; Doerk, 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, A-M ; Buecher, B ; Caputo, S ; Dupre, A ; Fourme, E ; Gauthier-Villars, M ; Golmard, L ; Le Mentec, M ; Moncoutier, V ; de Pauw, A ; Saule, C ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Bressac-de-Paillerets, B ; Caron, O ; Guillaud-Bataille, M ; Bignon, Y-J ; Uhrhammer, N ; Bonadona, V ; Lasset, C ; Berthet, P ; Castera, L ; Vaur, D ; Bourdon, V ; Nogues, C ; Noguchi, T ; Popovici, C ; Remenieras, A ; Sobol, H ; Coupier, I ; Pujol, P ; Adenis, C ; Dumont, A ; Revillion, F ; Muller, D ; Barouk-Simonet, E ; Bonnet, F ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Guimbaud, R ; Feillel, V ; Toulas, C ; Dreyfus, H ; Leroux, CD ; Peysselon, M ; Rebischung, C ; Legrand, C ; Baurand, A ; Bertolone, G ; Coron, F ; Faivre, L ; Jacquot, C ; Lizard, S ; Kientz, C ; Lebrun, M ; Prieur, F ; Fert-Ferrer, S ; Mari, V ; Venat-Bouvet, L ; Bezieau, S ; Delnatte, C ; Mortemousque, I ; Colas, C ; Coulet, F ; Soubrier, F ; Warcoin, M ; Bronner, M ; Sokolowska, J ; Collonge-Rame, M-A ; Damette, A ; Gesta, P ; Lallaoui, H ; Chiesa, J ; Molina-Gomes, D ; Ingster, O ; Manouvrier-Hanu, S ; Lejeune, S ; Aghmesheh, M ; Greening, S ; Amor, D ; Gattas, M ; Botes, L ; Buckley, M ; Friedlander, M ; Koehler, J ; Meiser, B ; Saleh, M ; Salisbury, E ; Trainer, A ; Tucker, K ; Antill, Y ; Dobrovic, A ; Fellows, A ; Fox, S ; Harris, M ; Nightingale, S ; Phillips, K ; Sambrook, J ; Thorne, H ; Armitage, S ; Arnold, L ; Kefford, R ; Kirk, J ; Rickard, E ; Bastick, P ; Beesley, J ; Hayward, N ; Spurdle, A ; Walker, L ; Beilby, J ; Saunders, C ; Bennett, I ; Blackburn, A ; Bogwitz, M ; Gaff, C ; Lindeman, G ; Pachter, N ; Scott, C ; Sexton, A ; Visvader, J ; Taylor, J ; Winship, I ; Brennan, M ; Brown, M ; French, J ; Edwards, S ; Burgess, M ; Burke, J ; Patterson, B ; Butow, P ; Culling, B ; Caldon, L ; Callen, D ; Chauhan, D ; Eisenbruch, M ; Heiniger, L ; Chauhan, M ; Christian, A ; Dixon, J ; Kidd, A ; Cohen, P ; Colley, A ; Fenton, G ; Crook, A ; Dickson, R ; Field, M ; Cui, J ; Cummings, M ; Dawson, S-J ; DeFazio, A ; Delatycki, M ; Dudding, T ; Edkins, T ; Farshid, G ; Flanagan, J ; Fong, P ; Forrest, L ; Gallego-Ortega, D ; George, P ; Gill, G ; Kollias, J ; Haan, E ; Hart, S ; Jenkins, M ; Hunt, C ; Lakhani, S ; Lipton, L ; Lobb, L ; Mann, G ; McLachlan, SA ; O'Connell, S ; O'Sullivan, S ; Pieper, E ; Robinson, B ; Saunus, J ; Scott, E ; Shelling, A ; Williams, R ; Young, MA (Springer Nature, 2019-11-01)
    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.
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    Is RNASEL:p.Glu265*a modifier of early-onset breast cancer risk for carriers of high-risk mutations?
    Nguyen-Dumont, T ; Teo, ZL ; Hammet, F ; Roberge, A ; Mahmoodi, M ; Tsimiklis, H ; Park, DJ ; Pope, BJ ; Lonie, A ; Kapuscinski, MK ; Mahmood, K ; Goldgar, DE ; Giles, GG ; Winship, I ; Hopper, JL ; Southey, MC (BIOMED CENTRAL LTD, 2018-02-08)
    BACKGROUND: Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. METHODS: In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. RESULTS: RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations. CONCLUSION: Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early-onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report.