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. 2014 Apr 3;10(4):e1004256.
doi: 10.1371/journal.pgen.1004256. eCollection 2014 Apr.

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Ana Osorio  1 , Roger L Milne  2 , Karoline Kuchenbaecker  3 , Tereza Vaclová  4 , Guillermo Pita  5 , Rosario Alonso  5 , Paolo Peterlongo  6 , Ignacio Blanco  7 , Miguel de la Hoya  8 , Mercedes Duran  9 , Orland Díez  10 , Teresa Ramón Y Cajal  11 , Irene Konstantopoulou  12 , Cristina Martínez-Bouzas  13 , Raquel Andrés Conejero  14 , Penny Soucy  15 , Lesley McGuffog  3 , Daniel Barrowdale  3 , Andrew Lee  3 ; SWE-BRCA  16 ; Brita Arver  17 , Johanna Rantala  18 , Niklas Loman  19 , Hans Ehrencrona  20 , Olufunmilayo I Olopade  21 , Mary S Beattie  22 , Susan M Domchek  23 , Katherine Nathanson  23 , Timothy R Rebbeck  24 , Banu K Arun  25 , Beth Y Karlan  26 , Christine Walsh  26 , Jenny Lester  26 , Esther M John  27 , Alice S Whittemore  28 , Mary B Daly  29 , Melissa Southey  30 , John Hopper  31 , Mary B Terry  32 , Saundra S Buys  33 , Ramunas Janavicius  34 , Cecilia M Dorfling  35 , Elizabeth J van Rensburg  35 , Linda Steele  36 , Susan L Neuhausen  36 , Yuan Chun Ding  36 , Thomas V O Hansen  37 , Lars Jønson  37 , Bent Ejlertsen  38 , Anne-Marie Gerdes  39 , Mar Infante  9 , Belén Herráez  5 , Leticia Thais Moreno  5 , Jeffrey N Weitzel  40 , Josef Herzog  40 , Kisa Weeman  40 , Siranoush Manoukian  41 , Bernard Peissel  41 , Daniela Zaffaroni  41 , Giulietta Scuvera  41 , Bernardo Bonanni  42 , Frederique Mariette  43 , Sara Volorio  43 , Alessandra Viel  44 , Liliana Varesco  45 , Laura Papi  46 , Laura Ottini  47 , Maria Grazia Tibiletti  48 , Paolo Radice  49 , Drakoulis Yannoukakos  12 , Judy Garber  50 , Steve Ellis  3 , Debra Frost  3 , Radka Platte  3 , Elena Fineberg  3 , Gareth Evans  51 , Fiona Lalloo  51 , Louise Izatt  52 , Ros Eeles  53 , Julian Adlard  54 , Rosemarie Davidson  55 , Trevor Cole  56 , Diana Eccles  57 , Jackie Cook  58 , Shirley Hodgson  59 , Carole Brewer  60 , Marc Tischkowitz  61 , Fiona Douglas  62 , Mary Porteous  63 , Lucy Side  64 , Lisa Walker  65 , Patrick Morrison  66 , Alan Donaldson  67 , John Kennedy  68 , Claire Foo  69 , Andrew K Godwin  70 , Rita Katharina Schmutzler  71 , Barbara Wappenschmidt  71 , Kerstin Rhiem  71 , Christoph Engel  72 , Alfons Meindl  73 , Nina Ditsch  73 , Norbert Arnold  74 , Hans Jörg Plendl  75 , Dieter Niederacher  76 , Christian Sutter  77 , Shan Wang-Gohrke  78 , Doris Steinemann  79 , Sabine Preisler-Adams  80 , Karin Kast  81 , Raymonda Varon-Mateeva  82 , Andrea Gehrig  83 , Dominique Stoppa-Lyonnet  84 , Olga M Sinilnikova  85 , Sylvie Mazoyer  86 , Francesca Damiola  86 , Bruce Poppe  87 , Kathleen Claes  87 , Marion Piedmonte  88 , Kathy Tucker  89 , Floor Backes  90 , Gustavo Rodríguez  91 , Wendy Brewster  92 , Katie Wakeley  93 , Thomas Rutherford  94 , Trinidad Caldés  8 , Heli Nevanlinna  95 , Kristiina Aittomäki  95 , Matti A Rookus  96 , Theo A M van Os  97 , Lizet van der Kolk  98 , J L de Lange  96 , Hanne E J Meijers-Heijboer  99 , A H van der Hout  100 , Christi J van Asperen  101 , Encarna B Gómez Garcia  102 , Nicoline Hoogerbrugge  103 , J Margriet Collée  104 , Carolien H M van Deurzen  105 , Rob B van der Luijt  106 , Peter Devilee  107 ; HEBON  108 ; Edith Olah  109 , Conxi Lázaro  110 , Alex Teulé  7 , Mireia Menéndez  110 , Anna Jakubowska  111 , Cezary Cybulski  111 , Jacek Gronwald  111 , Jan Lubinski  111 , Katarzyna Durda  111 , Katarzyna Jaworska-Bieniek  112 , Oskar Th Johannsson  113 , Christine Maugard  114 , Marco Montagna  115 , Silvia Tognazzo  115 , Manuel R Teixeira  116 , Sue Healey  117 ; KConFab Investigators  118 ; Curtis Olswold  119 , Lucia Guidugli  120 , Noralane Lindor  121 , Susan Slager  119 , Csilla I Szabo  122 , Joseph Vijai  123 , Mark Robson  124 , Noah Kauff  124 , Liying Zhang  125 , Rohini Rau-Murthy  124 , Anneliese Fink-Retter  126 , Christian F Singer  126 , Christine Rappaport  126 , Daphne Geschwantler Kaulich  126 , Georg Pfeiler  126 , Muy-Kheng Tea  126 , Andreas Berger  126 , Catherine M Phelan  127 , Mark H Greene  128 , Phuong L Mai  128 , Flavio Lejbkowicz  129 , Irene Andrulis  130 , Anna Marie Mulligan  131 , Gord Glendon  132 , Amanda Ewart Toland  133 , Anders Bojesen  134 , Inge Sokilde Pedersen  135 , Lone Sunde  136 , Mads Thomassen  137 , Torben A Kruse  137 , Uffe Birk Jensen  136 , Eitan Friedman  138 , Yael Laitman  138 , Shani Paluch Shimon  138 , Jacques Simard  139 , Douglas F Easton  3 , Kenneth Offit  123 , Fergus J Couch  140 , Georgia Chenevix-Trench  117 , Antonis C Antoniou  3 , Javier Benitez  141
Affiliations

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Ana Osorio et al. PLoS Genet. .

Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. p-values of association (−log10 scale) with breast cancer risk in BRCA2 carriers for genotyped and imputed SNPs in the NEIL2 gene.
SNP rs1466785 is indicated with a purple arrow and the best causal imputed SNPs, rs804276 and rs804271 are indicated with a red arrow. Colors represent the pariwise r2. Plot generated with LocusZoom (http://csg.sph.umich.edu/locuszoom/).
See this image and copyright information in PMC

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