DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case–control studies

Abstract

The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility. However, association studies on the XRCC3 polymorphisms (4541A4G, Thr 241 Met, 17893A4G) in cancer have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported associations. Forty eight eligible case-control studies including 24 975 cancer patients and 34 209 controls were selected for our meta-analysis. Overall, individuals carrying the XRCC3 Met/Met genotype showed a small cancer risk under a recessive genetic model. The subgroup and metaregression analysis demonstrated different scenarios concerning the XRCC3 Met/Met genotype's role in cancer susceptibility for different subgroups. Specially, there was a significantly increased risk of breast cancer (OR, 1.14; P ¼ 0.0004; 95% CI, 1.06 -1.23; P ¼ 0.37 for heterogeneity), elevated but not significant risk of cancer for head and neck, bladder, surprisingly, a significantly decreased risk of non-melanoma skin cancer (OR, 0.76; P ¼ 0.007; 95% CI, 0.62-0.93; P ¼ 0.61 for heterogeneity). A significantly elevated risk of cancer was observed in population-based case-control studies but not in nested or hospital based studies. Similarly, we found a significantly increased risk of cancer for A4541G and a decreased risk for A17893G under dominant genetic models. Our meta-analysis results support that the XRCC3 might represent a lowpenetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer. A single larger study should be required to further evaluate gene -gene and geneenvironment interactions on XRCC3 polymorphisms and tissue-specific cancer risk in an ethnicity specific population.

Genetic polymorphisms in double-strand break DNA repair genes associated with risk of oral premalignant lesions

“…Factors such as study design, sample size, cancer sites, population heterogeneity, and the biological complexity of low-penetrance cancer susceptibility genes may explain the observed discrepancies. In keeping with our results showing a protective role for the variant allele of XRCC3 A17893G in OPL development, a meta-analysis of a total of 24,795 cancer patients and 34,209 controls reported a significantly reduced cancer risk associated with this allele under a dominant genetic model with an OR of 0.92 (95% CI 0.87-0.96, P=0.0004) (41). Whether this intronic SNP has any functional impact on the splicing of the XRCC3 transcript needs to be further evaluated through the assessment of XRCC3 mRNA levels in subjects with different genotypes.…”

XRCC3 Thr241Met polymorphism and breast cancer risk: a meta-analysis

“…Out of the 55 abstracts retrieved through the search criteria, 25 were irrelevant, four articles [8][9][10][11] were excluded because they were conducted on overlapping populations with other eligible studies [2,3,5,12] (these excluded articles represent smaller studies performed on subsets of larger eligible studies), one study [13] was excluded given that it has not included controls in its study design, three articles [4,14,15] were reviews/meta-analyses, and three studies [16][17][18] were excluded due to other reasons (two of them [16,17] were excluded due to reporting reasons, i.e. no reporting of the relevant genotype frequencies, whereas the other [18] was excluded for examining the association between other XRCC3 polymorphisms and premenopausal breast cancer risk).…”

Association between the XRCC3 Thr241Met Polymorphism and Risk of Colorectal Cancer: a Meta Analysis of 5,193 Cases and 6,645 Controls

“…The discrepancy may be due to the different genotype penetrance of XRCC3 Thr241Met in different ethnicities (Shizhong Han et al, 2006). Thus far, little has been known about the potential causes needing further investigation.…”