Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Dobrovic, Alexander × Author: McNally, Orla × End date: 2019 × Start date: 2012 × Type: Journal Article ×

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    Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
    Kondrashova, O ; Topp, M ; Nesic, K ; Lieschke, E ; Ho, G-Y ; Harrell, M ; Zapparoli, G ; Hadley, A ; Holian, R ; Boehm, E ; Heong, V ; Sanij, E ; Pearson, RB ; Krais, JJ ; Johnson, N ; McNally, O ; Ananda, S ; Alsop, K ; Hutt, KJ ; Kaufmann, SH ; Lin, KK ; Harding, TC ; Traficante, N ; deFazio, A ; McNeish, LA ; Bowtell, DD ; Swisher, EM ; Dobrovic, A ; Wakefield, MJ ; Scott, CL ; Chenevix-Trench, G ; Green, A ; Webb, P ; Gertig, D ; Fereday, S ; Moore, S ; Hung, J ; Harrap, K ; Sadkowsky, T ; Pandeya, N ; Malt, M ; Mellon, A ; Robertson, R ; Vanden Bergh, T ; Jones, M ; Mackenzie, P ; Maidens, J ; Nattress, K ; Chiew, YE ; Stenlake, A ; Sullivan, H ; Alexander, B ; Ashover, P ; Brown, S ; Corrish, T ; Green, L ; Jackman, L ; Ferguson, K ; Martin, K ; Martyn, A ; Ranieri, B ; White, J ; Jayde, V ; Mamers, P ; Bowes, L ; Galletta, L ; Giles, D ; Hendley, J ; Schmidt, T ; Shirley, H ; Ball, C ; Young, C ; Viduka, S ; Tran, H ; Bilic, S ; Glavinas, L ; Brooks, J ; Stuart-Harris, R ; Kirsten, F ; Rutovitz, J ; Clingan, P ; Glasgow, A ; Proietto, A ; Braye, S ; Otton, G ; Shannon, J ; Bonaventura, T ; Stewart, J ; Begbie, S ; Friedlander, M ; Bell, D ; Baron-Hay, S ; Ferrier, A ; Gard, G ; Nevell, D ; Pavlakis, N ; Valmadre, S ; Young, B ; Camaris, C ; Crouch, R ; Edwards, L ; Hacker, N ; Marsden, D ; Robertson, G ; Beale, P ; Beith, J ; Carter, J ; Dalrymple, C ; Houghton, R ; Russell, P ; Links, M ; Grygiel, J ; Hill, J ; Brand, A ; Byth, K ; Jaworski, R ; Harnett, P ; Sharma, R ; Wain, G ; Ward, B ; Papadimos, D ; Crandon, A ; Cummings, M ; Horwood, K ; Obermair, A ; Perrin, L ; Wyld, D ; Nicklin, J ; Davy, M ; Oehler, MK ; Hall, C ; Dodd, T ; Healy, T ; Pittman, K ; Henderson, D ; Miller, J ; Pierdes, J ; Blomfield, P ; Challis, D ; Mclntosh, R ; Parker, A ; Brown, B ; Rome, R ; Allen, D ; Grant, P ; Hyde, S ; Laurie, R ; Robbie, M ; Healy, D ; Jobling, T ; Manolitsas, T ; McNealage, J ; Rogers, P ; Susil, B ; Sumithran, E ; Simpson, I ; Phillips, K ; Rischin, D ; Fox, S ; Johnson, D ; Lade, S ; Loughrey, M ; O'Callaghan, N ; Murray, W ; Waring, P ; Billson, V ; Pyman, J ; Neesham, D ; Quinn, M ; Underhill, C ; Bell, R ; Ng, LF ; Blum, R ; Ganju, V ; Hammond, I ; Leung, Y ; McCartney, A ; Buck, M ; Haviv, I ; Purdie, D ; Whiteman, D ; Zeps, N (NATURE PUBLISHING GROUP, 2018-09-28)
    Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
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    RAD51B in Familial Breast Cancer
    Pelttari, LM ; Khan, S ; Vuorela, M ; Kiiski, JI ; Vilske, S ; Nevanlinna, V ; Ranta, S ; Schleutker, J ; Winqvist, R ; Kallioniemi, A ; Doerk, T ; Bogdanova, NV ; Figueroa, J ; Pharoah, PDP ; Schmidt, MK ; Dunning, AM ; Garcia-Closas, M ; Bolla, MK ; Dennis, J ; Michailidou, K ; Wang, Q ; Hopper, JL ; Southey, MC ; Rosenberg, EH ; Fasching, PA ; Beckmann, MW ; Peto, J ; dos-Santos-Silva, I ; Sawyer, EJ ; Tomlinson, I ; Burwinkel, B ; Surowy, H ; Guenel, P ; Truong, T ; Bojesen, SE ; Nordestgaard, BG ; Benitez, J ; Gonzalez-Neira, A ; Neuhausen, SL ; Anton-Culver, H ; Brenner, H ; Arndt, V ; Meindl, A ; Schmutzler, RK ; Brauch, H ; Bruening, T ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Hartikainen, JM ; Chenevix-Trench, G ; Van Dyck, L ; Janssen, H ; Chang-Claude, J ; Rudolph, A ; Radice, P ; Peterlongo, P ; Hallberg, E ; Olson, JE ; Giles, GG ; Milne, RL ; Haiman, CA ; Schumacher, F ; Simard, J ; Dumont, M ; Kristensen, V ; Borresen-Dale, A-L ; Zheng, W ; Beeghly-Fadiel, A ; Grip, M ; Andrulis, IL ; Glendon, G ; Devilee, P ; Seynaeve, C ; Hooning, MJ ; Collee, M ; Cox, A ; Cross, SS ; Shah, M ; Luben, RN ; Hamann, U ; Torres, D ; Jakubowska, A ; Lubinski, J ; Couch, FJ ; Yannoukakos, D ; Orr, N ; Swerdlow, A ; Darabi, H ; Li, J ; Czene, K ; Hall, P ; Easton, DF ; Mattson, J ; Blomqvist, C ; Aittomaki, K ; Nevanlinna, H ; Brusgaard, K (PUBLIC LIBRARY SCIENCE, 2016-05-05)
    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.