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. 2020 Feb 1;80(3):624-638.
doi: 10.1158/0008-5472.CAN-19-1840. Epub 2019 Nov 13.

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Vivek L Patel  1 , Evan L Busch  2   3 , Tara M Friebel  2   4 , Angel Cronin  4 , Goska Leslie  5 , Lesley McGuffog  5 , Julian Adlard  6 , Simona Agata  7 , Bjarni A Agnarsson  8   9 , Munaza Ahmed  10 , Kristiina Aittomäki  11 , Elisa Alducci  7 , Irene L Andrulis  12   13 , Adalgeir Arason  8   14 , Norbert Arnold  15 , Grazia Artioli  16 , Brita Arver  17 , Bernd Auber  18 , Jacopo Azzollini  19 , Judith Balmaña  20 , Rosa B Barkardottir  8   14 , Daniel R Barnes  5 , Alicia Barroso  21 , Daniel Barrowdale  5 , Muriel Belotti  22 , Javier Benitez  23   24 , Birgitte Bertelsen  25 , Marinus J Blok  26 , Istvan Bodrogi  27 , Valérie Bonadona  28 , Bernardo Bonanni  29 , Davide Bondavalli  29 , Susanne E Boonen  30 , Julika Borde  31   32   33 , Ake Borg  34 , Angela R Bradbury  35 , Angela Brady  36 , Carole Brewer  37 , Joan Brunet  38 , Bruno Buecher  22 , Saundra S Buys  39 , Santiago Cabezas-Camarero  40 , Trinidad Caldés  41 , Almuth Caliebe  42 , Maria A Caligo  43 , Mariarosaria Calvello  29 , Ian G Campbell  44   45 , Ileana Carnevali  46 , Estela Carrasco  20 , Tsun L Chan  47   48 , Annie T W Chu  47 , Wendy K Chung  49 , Kathleen B M Claes  50 , Gemo Study Collaborators  22 , Embrace Collaborators  5 , Jackie Cook  51 , Laura Cortesi  52 , Fergus J Couch  53 , Mary B Daly  54 , Giuseppe Damante  55 , Esther Darder  38 , Rosemarie Davidson  56 , Miguel de la Hoya  41 , Lara Della Puppa  57 , Joe Dennis  5 , Orland Díez  58 , Yuan Chun Ding  59 , Nina Ditsch  60 , Susan M Domchek  35 , Alan Donaldson  61 , Bernd Dworniczak  62 , Douglas F Easton  5   63 , Diana M Eccles  64 , Rosalind A Eeles  65 , Hans Ehrencrona  66 , Bent Ejlertsen  67 , Christoph Engel  68   69 , D Gareth Evans  70   71 , Laurence Faivre  72 , Ulrike Faust  73 , Lídia Feliubadaló  74 , Lenka Foretova  75 , Florentia Fostira  76 , George Fountzilas  77 , Debra Frost  5 , Vanesa García-Barberán  41 , Pilar Garre  41 , Marion Gauthier-Villars  22 , Lajos Géczi  27 , Andrea Gehrig  78 , Anne-Marie Gerdes  79 , Paul Gesta  80 , Giuseppe Giannini  81 , Gord Glendon  12 , Andrew K Godwin  82 , David E Goldgar  83 , Mark H Greene  84 , Angelica M Gutierrez-Barrera  85 , Eric Hahnen  32   33 , Ute Hamann  86 , Jan Hauke  31   32   33 , Natalie Herold  31   32   33 , Frans B L Hogervorst  87 , Ellen Honisch  88 , John L Hopper  89 , Peter J Hulick  90   91 , KConFab Investigators  44   45 , Hebon Investigators  92 , Louise Izatt  93 , Agnes Jager  94 , Paul James  45   95 , Ramunas Janavicius  96 , Uffe Birk Jensen  97 , Thomas Dyrso Jensen  98 , Oskar Th Johannsson  99 , Esther M John  100 , Vijai Joseph  101 , Eunyoung Kang  102 , Karin Kast  103 , Johanna I Kiiski  104 , Sung-Won Kim  105 , Zisun Kim  106 , Kwang-Pil Ko  107 , Irene Konstantopoulou  76 , Gero Kramer  108 , Lotte Krogh  109 , Torben A Kruse  109 , Ava Kwong  47   110   111 , Mirjam Larsen  31   32   33 , Christine Lasset  28 , Charlotte Lautrup  112 , Conxi Lazaro  74 , Jihyoun Lee  113 , Jong Won Lee  114 , Min Hyuk Lee  113 , Johannes Lemke  115 , Fabienne Lesueur  22   116   117   118 , Annelie Liljegren  17 , Annika Lindblom  119   120 , Patricia Llovet  41 , Adria Lopez-Fernández  20 , Irene Lopez-Perolio  41 , Victor Lorca  41 , Jennifer T Loud  84 , Edmond S K Ma  47   48 , Phuong L Mai  121 , Siranoush Manoukian  19 , Veronique Mari  122 , Lynn Martin  123 , Laura Matricardi  7 , Noura Mebirouk  22   116   117   118 , Veronica Medici  52 , Hanne E J Meijers-Heijboer  124 , Alfons Meindl  60 , Arjen R Mensenkamp  125 , Clare Miller  126 , Denise Molina Gomes  127 , Marco Montagna  7 , Thea M Mooij  128 , Lidia Moserle  7 , Emmanuelle Mouret-Fourme  22 , Anna Marie Mulligan  129   130 , Katherine L Nathanson  35 , Marie Navratilova  75 , Heli Nevanlinna  104 , Dieter Niederacher  89 , Finn C Cilius Nielsen  25 , Liene Nikitina-Zake  131 , Kenneth Offit  102   132 , Edith Olah  133 , Olufunmilayo I Olopade  134 , Kai-Ren Ong  135 , Ana Osorio  23   24 , Claus-Eric Ott  136 , Domenico Palli  137 , Sue K Park  138   139   140 , Michael T Parsons  141 , Inge Sokilde Pedersen  142 , Bernard Peissel  19 , Ana Peixoto  143 , Pedro Pérez-Segura  40 , Paolo Peterlongo  144 , Annabeth Høgh Petersen  98 , Mary E Porteous  145 , Miguel Angel Pujana  146 , Paolo Radice  147 , Juliane Ramser  148 , Johanna Rantala  149 , Muhammad U Rashid  86   150 , Kerstin Rhiem  31   32   33 , Piera Rizzolo  81 , Mark E Robson  132 , Matti A Rookus  128 , Caroline M Rossing  25 , Kathryn J Ruddy  151 , Catarina Santos  143 , Claire Saule  22 , Rosa Scarpitta  152 , Rita K Schmutzler  32   33 , Hélène Schuster  153 , Leigha Senter  154 , Caroline M Seynaeve  94 , Payal D Shah  35 , Priyanka Sharma  155 , Vivian Y Shin  110 , Valentina Silvestri  81 , Jacques Simard  156 , Christian F Singer  157 , Anne-Bine Skytte  98 , Katie Snape  158 , Angela R Solano  159 , Penny Soucy  155 , Melissa C Southey  160   161 , Amanda B Spurdle  141 , Linda Steele  59 , Doris Steinemann  162 , Dominique Stoppa-Lyonnet  22   163   164 , Agostina Stradella  165 , Lone Sunde  97 , Christian Sutter  166 , Yen Y Tan  167 , Manuel R Teixeira  143   168 , Soo Hwang Teo  169   170 , Mads Thomassen  109 , Maria Grazia Tibiletti  46 , Marc Tischkowitz  171   172 , Silvia Tognazzo  7 , Amanda E Toland  173 , Stefania Tommasi  174 , Diana Torres  86   175 , Angela Toss  52 , Alison H Trainer  95 , Nadine Tung  176 , Christi J van Asperen  177 , Frederieke H van der Baan  128 , Lizet E van der Kolk  87 , Rob B van der Luijt  178 , Liselotte P van Hest  179 , Liliana Varesco  180 , Raymonda Varon-Mateeva  136 , Alessandra Viel  57 , Jeroen Vierstraete  50 , Roberta Villa  19 , Anna von Wachenfeldt  17 , Philipp Wagner  181 , Shan Wang-Gohrke  182 , Barbara Wappenschmidt  32   33 , Jeffrey N Weitzel  183 , Greet Wieme  50 , Siddhartha Yadav  151 , Drakoulis Yannoukakos  76 , Sook-Yee Yoon  184 , Cristina Zanzottera  19 , Kristin K Zorn  121 , Anthony V D'Amico  1 , Matthew L Freedman  4 , Mark M Pomerantz  4 , Georgia Chenevix-Trench  141 , Antonis C Antoniou  5 , Susan L Neuhausen  59 , Laura Ottini  81 , Henriette Roed Nielsen  109 , Timothy R Rebbeck  185   4
Affiliations

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Vivek L Patel et al. Cancer Res. .

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

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Conflict of interest statement

Financial support and conflict of interest statements are included at the end of the manuscript.

Figures

Figure 1:
Figure 1:. BRCA1 Pathogenic Sequence Variant Distribution
The x-axis displays the amino acid sequence of the BRCA1 gene. The violet markers indicate the position of PSVs found in the BRCA1 PSV carriers. The vertical position of the markers on the y-axis indicates the frequency of the PSV found in the cohort. Additionally, the blue and tan bars with corresponding axis markers delineate the bins of the BRCA1 PSVs that were created using the “decile” binning strategy and the “functional” binning strategy. Orange and light blue bars indicate the position of breast and ovarian cancer cluster regions, respectively, as identified in the CIMBA breast cancer cohort (Rebbeck et al. JAMA 2015). Lastly, known functional domains within the BRCA1 gene are highlighted. A. Distribution of total BRCA1 PSVs in carriers, B. Distribution of BRCA1 PSVs in carriers who did not develop prostate cancer, C. Distribution of BRCA1 PSVs in carriers who developed prostate cancer.
Figure 2.
Figure 2.. BRCA2 Pathogenic Sequence Variant Distribution
The x-axis displays the amino acid sequence of the BRCA2 gene. The violet markers indicate the position of PSVs found in the BRCA2 PSV carriers. The vertical position of the markers on the y-axis indicates the frequency of the PSV found in the cohort. Additionally, the blue and tan bars with corresponding axis markers delineate the bins of the BRCA2 PSVs that were created using the “decile” binning strategy and the “functional” binning strategy. Orange and light blue bars indicate the position of breast and ovarian cancer cluster regions, respectively, as identified in the CIMBA breast cancer cohort (Rebbeck et al. JAMA 2015). Lastly, known functional domains within the BRCA2 gene are highlighted. A. Distribution of total BRCA2 PSVs in carriers, B. Distribution of BRCA2 PSVs in carriers who did not develop prostate cancer, C. Distribution of BRCA2 PSVs in carriers who developed prostate cancer.
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