Prevalence of BER gene polymorphisms in sporadic breast cancer

Abstract

Abstract. Studies suggest that breast cancer is initiated by the induction of somatic mutations from errors in the base excision repair (BER) of endogenous estrogen-induced abasic sites. If so, the inheritance of certain polymorphic mutations in BER genes involved in the incorporation and management of such errors should increase the risk of breast cancer. To test this hypothesis, we examined breast tissues from 48 women (controls, histopathologically normal tissue from reduction mammoplasty) and 40 women with breast cancer (breast tumor-adjacent, histopathologically normal tissues) for the presence of reported polymorphic mutations in four BER genes. The breast tissues were obtained from the Cooperative Human Tissue Network-western division and from the University of Nebraska Medical Center. Using PCR-RFLP procedures, the XRCC1 gene was examined for Arg194Trp and Arg399Gln, APE1 for Asp148Glu, LIG3α for Arg780His and PARP1 for Pro377Ser mutations. The women in this study carried only the XRCC1 Arg399Gln polymorphism. This result was surprising because APE1 148Glu was reported to be frequently inherited (allele frequency, 0.47-0.495) by USA and European women. Thus, the USA women in our study are genetically different from those in the previous studies. Among the control women, 21 (43.75%) were Arg/ Arg wild-types, 20 (41.67%) were Arg/Gln heterozygotes and 7 (14.6%) were Gln/Gln homozygotes. Among the breast cancer cases, 11 (27.5%) were Arg/Arg wild-types, 16 (40%) were Arg/Gln heterozygotes and 13 (32.5%) were Gln/Gln homozygotes. Thus, the Gln allele was significantly more frequent in breast cancer cases (allele frequency, 0.52) than in controls (allele frequency, 0.35), suggesting that XRCC1 399Gln may enhance the risk of breast cancer. IntroductionBase excision repair (BER) has long been thought of as the guardian of the genome, responsible only for minimizing somatic mutations by correctly repairing endogenous base loss in DNA (1). Carcinogens that form abasic sites have been shown to induce errors in BER, forming mutations that lead to cancer (2-5).In breast cancer, the mutations can be induced by errors in the repair of the abasic sites generated by natural estrogens (4-6). In this mechanism, estrogen metabolism in the breast is altered, leading to an abnormal increase in the levels of catechol quinones, especially the estrogen-3,4-quinones, which react with DNA and almost exclusively form depurinating adducts (7-9). These adducts spontaneously dissociate from DNA to form abasic sites and generate mutations by BER errors (4,5).If erroneous BER is a mechanism of breast cancer, the polymorphic mutations in BER genes that increase mutagenesis would be expected to modify breast cancer risk. There is a limited amount of information about BER gene polymorphisms in breast cancer (10,11). Briefly, OGG1 Ser326Cys, APE1 Asp148Glu, PARP1 Val276Trp and LIG3α Arg780His did not show any significant association with breast cancer (12)(13)(14). On the other hand, in some studies, polymorphisms in the XRCC1 gene (Arg194...

XRCC1 Gene Polymorphisms and Breast Cancer Risk: A Systematic Review and Meta-analysis Study

“…Through a detailed search of databases, 53 literatures were identified for further evaluation (Figure 1) (Kim et al, 2002b;Han et al, 2003;Moullan et al, 2003;Shu et al, 2003;Smith et al, 2003a;Smith et al, 2003b;Deligezer and Dalay, 2004;Figueiredo et al, 2004;Försti et al, 2004;Huang et al, 2004;Chacko et al, 2005;Dufloth et al, 2005;Metsola et al, 2005;Patel et al, 2005b;Shen et al, 2005;Brewster et al, 2006;Bu et al, 2006;Pachkowski et al, 2006b;Thyagarajan et al, 2006;Zhai et al, 2006;Zhang et al, 2006b;Costa et al, 2007;Silva et al, 2007b;Ali et al, 2008;Kipikasova et al, 2008;Loizidou et al, 2008;Mitra et al, 2008;Saadat et al, 2008;Sangrajrang et al, 2008;Smith et al, 2008;Sobczuk et al, 2009a;Syamala et al, 2009;Jakubowska XRCC1 Gene Polymorphisms and Breast Cancer Risk: A Systematic Review and Meta- , 2010;Jelonek et al, 2010;Ming-Shiean et al, 2010;Romanowicz et al, 2010;Santos et al, 2010;…”

Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population

“…It is undeniable that polymorphisms of DNA repair systems participate in the carcinogenesis process, as mentioned before in the first part of Section 4 . Extensive studies suggest that these polymorphisms play a role in almost all types of cancer [ 37 – 40 ], including colorectal cancer [ 29 , 41 ]. The genetic polymorphisms of MMR system appear to participate in the pathogenesis of hereditary nonpolyposis colorectal cancer [ 42 , 43 ], and a growing body of evidence suggests their involvement in the BER system [ 44 , 45 ], but reports concerning the NER system are inconclusive, with some confirming the link [ 46 ] and others denying it [ 47 ].…”

Genomic instability and the selection of treatments for cancer

“…It has been suggested that polymorphisms of a number of BER genes, XRCC1, APE1 and ADPRT , confer risks for differentiated thyroid cancer and its progression 81. Similarly, BER gene polymorphisms have been associated with risk of sporadic breast cancer, including XRCC1 399Gln 82. Polymorphisms of the NER genes, ERCC1 and XPD , are associated with oesophageal adenocarcinoma risk 83, 84.…”