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

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.

SUBMITTER: Osorio A

PROVIDER: S-EPMC3974638 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Osorio Ana A Milne Roger L RL Kuchenbaecker Karoline K Vaclová Tereza T Pita Guillermo G Alonso Rosario R Peterlongo Paolo P Blanco Ignacio I de la Hoya Miguel M Duran Mercedes M Díez Orland O Ramón Y Cajal Teresa T Konstantopoulou Irene I Martínez-Bouzas Cristina C Andrés Conejero Raquel R Soucy Penny P McGuffog Lesley L Barrowdale Daniel D Lee Andrew A Arver Brita B Rantala Johanna J Loman Niklas N Ehrencrona Hans H Olopade Olufunmilayo I OI Beattie Mary S MS Domchek Susan M SM Nathanson Katherine K Rebbeck Timothy R TR Arun Banu K BK Karlan Beth Y BY Walsh Christine C Lester Jenny J John Esther M EM Whittemore Alice S AS Daly Mary B MB Southey Melissa M Hopper John J Terry Mary B MB Buys Saundra S SS Janavicius Ramunas R Dorfling Cecilia M CM van Rensburg Elizabeth J EJ Steele Linda L Neuhausen Susan L SL Ding Yuan Chun YC Hansen Thomas V O TV Jønson Lars L Ejlertsen Bent B Gerdes Anne-Marie AM Infante Mar M Herráez Belén B Moreno Leticia Thais LT Weitzel Jeffrey N JN Herzog Josef J Weeman Kisa K Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Scuvera Giulietta G Bonanni Bernardo B Mariette Frederique F Volorio Sara S Viel Alessandra A Varesco Liliana L Papi Laura L Ottini Laura L Tibiletti Maria Grazia MG Radice Paolo P Yannoukakos Drakoulis D Garber Judy J Ellis Steve S Frost Debra D Platte Radka R Fineberg Elena E Evans Gareth G Lalloo Fiona F Izatt Louise L Eeles Ros R Adlard Julian J Davidson Rosemarie R Cole Trevor T Eccles Diana D Cook Jackie J Hodgson Shirley S Brewer Carole C Tischkowitz Marc M Douglas Fiona F Porteous Mary M Side Lucy L Walker Lisa L Morrison Patrick P Donaldson Alan A Kennedy John J Foo Claire C Godwin Andrew K AK Schmutzler Rita Katharina RK Wappenschmidt Barbara B Rhiem Kerstin K Engel Christoph C Meindl Alfons A Ditsch Nina N Arnold Norbert N Plendl Hans Jörg HJ Niederacher Dieter D Sutter Christian C Wang-Gohrke Shan S Steinemann Doris D Preisler-Adams Sabine S Kast Karin K Varon-Mateeva Raymonda R Gehrig Andrea A Stoppa-Lyonnet Dominique D Sinilnikova Olga M OM Mazoyer Sylvie S Damiola Francesca F Poppe Bruce B Claes Kathleen K Piedmonte Marion M Tucker Kathy K Backes Floor F Rodríguez Gustavo G Brewster Wendy W Wakeley Katie K Rutherford Thomas T Caldés Trinidad T Nevanlinna Heli H Aittomäki Kristiina K Rookus Matti A MA van Os Theo A M TA van der Kolk Lizet L de Lange J L JL Meijers-Heijboer Hanne E J HE van der Hout A H AH van Asperen Christi J CJ Gómez Garcia Encarna B EB Hoogerbrugge Nicoline N Collée J Margriet JM van Deurzen Carolien H M CH van der Luijt Rob B RB Devilee Peter P Olah Edith E Lázaro Conxi C Teulé Alex A Menéndez Mireia M Jakubowska Anna A Cybulski Cezary C Gronwald Jacek J Lubinski Jan J Durda Katarzyna K Jaworska-Bieniek Katarzyna K Johannsson Oskar Th OT Maugard Christine C Montagna Marco M Tognazzo Silvia S Teixeira Manuel R MR Healey Sue S Olswold Curtis C Guidugli Lucia L Lindor Noralane N Slager Susan S Szabo Csilla I CI Vijai Joseph J Robson Mark M Kauff Noah N Zhang Liying L Rau-Murthy Rohini R Fink-Retter Anneliese A Singer Christian F CF Rappaport Christine C Geschwantler Kaulich Daphne D Pfeiler Georg G Tea Muy-Kheng MK Berger Andreas A Phelan Catherine M CM Greene Mark H MH Mai Phuong L PL Lejbkowicz Flavio F Andrulis Irene I Mulligan Anna Marie AM Glendon Gord G Toland Amanda Ewart AE Bojesen Anders A Pedersen Inge Sokilde IS Sunde Lone L Thomassen Mads M Kruse Torben A TA Jensen Uffe Birk UB Friedman Eitan E Laitman Yael Y Shimon Shani Paluch SP Simard Jacques J Easton Douglas F DF Offit Kenneth K Couch Fergus J FJ Chenevix-Trench Georgia G Antoniou Antonis C AC Benitez Javier J

PLoS genetics 20140403 4

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 ...[more]

PMID: 24698998

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Project description:A growing number of iron-sulfur (Fe-S) cluster cofactors have been identified in DNA repair proteins. MutY and its homologs are base excision repair (BER) glycosylases that prevent mutations associated with the common oxidation product of guanine (G), 8-oxo-7,8-dihydroguanine (OG) by catalyzing adenine (A) base excision from inappropriately formed OG:A mispairs. The finding of an [4Fe-4S]2+ cluster cofactor in MutY, Endonuclease III, and structurally similar BER enzymes was surprising and initially thought to represent an example of a purely structural role for the cofactor. However, in the two decades subsequent to the initial discovery, purification and in vitro analysis of bacterial MutYs and mammalian homologs, such as human MUTYH and mouse Mutyh, have demonstrated that proper Fe-S cluster coordination is required for OG:A substrate recognition and adenine excision. In addition, the Fe-S cluster in MutY has been shown to be capable of redox chemistry in the presence of DNA. The work in our laboratory aimed at addressing the importance of the MutY Fe-S cluster has involved a battery of approaches, with the overarching hypothesis that understanding the role(s) of the Fe-S cluster is intimately associated with understanding the biological and chemical properties of MutY and its unique damaged DNA substrate as a whole. In this chapter, we focus on methods of enzyme expression and purification, detailed enzyme kinetics, and DNA affinity assays. The methods described herein have not only been leveraged to provide insight into the roles of the MutY Fe-S cluster but have also been provided crucial information needed to delineate the impact of inherited variants of the human homolog MUTYH associated with a colorectal cancer syndrome known as MUTYH-associated polyposis or MAP. Notably, many MAP-associated variants have been found adjacent to the Fe-S cluster further underscoring the intimate relationship between the cofactor, MUTYH-mediated DNA repair, and disease.

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

Publications

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

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