Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses

Abstract

The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04-1.34) and 0.85 (0.73-0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05-1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04-1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10-1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59-1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene-gene interactions or associations in population subgroups will require even larger sample sizes.

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

“…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). As a result, 19 case-control articles [2,3,5,12,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]] (23 case-control studies, considering that Breast Cancer Association Consortium has more than one studies included) were included in this meta-analysis; 20 case-control studies on non-Chinese subjects (19,575 cases and 21,125 controls) and three case-control studies [3,24,29] on Chinese subjects (1,216 cases and 1,112 controls). Table 1 presents in detail the results of the meta-analysis.…”

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

“…For example, Kuschel and colleagues noted a significant protective effect of the variant allele of XRCC3 A17893G SNP against breast cancer in a UK population (30). This was later confirmed by two population-based studies, one conducted in the United States and the other in Poland (36). This variant allele has also been reported to confer a significantly decreased susceptibility to bladder (35), invasive ovarian (21), and upper aerodigestive (37) cancers.…”

“…For example, some studies have shown the variant allele to be associated with an increased risk for bladder, breast, and lung cancers (30,35,36,40), and these results were in agreement with the results from various functional assays showing that the variant allele was associated with an increased DNA adduct level and compromised capacity to repair X-ray-induced chromosome aberrations (42,43). In contrast, other groups found a lack of association of the T241M SNP with a risk for ovarian, skin, and endometrial cancers (20,21,39).…”

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

“…The variant T allele has been reported to be associated with a nonstatistically significant increased risk of squamous cell carcinoma of head and neck 37 and with a reduced risk of leukaemia, 17 whereas no association has been found in meningiomas, 38 and gastric cancer. [39][40][41] Moreover, conflicting results have been published on the associations with breast cancer, 16,21,22 lung cancer, 17,19,42 malignant melanoma 20,43,44 and bladder cancer. 17,18,45 It was also noted that the frequency of the XRCC3-241Met allele in our control group (5.9%) was similar to that previously reported in a Chinese population, 39 but quite different from that found in Caucasians and African Americans, suggesting that the Met allele frequency could vary by ethnicity.…”

“…14 The currently available high density of markers in specific chromosomal regions enables us to investigate possible involvement of a number of genes in the development of complex diseases using linkage disequilibrium (LD) to associate markers with disease occurrence at the population level. To our knowledge, few molecular epidemiologic studies have been published on cancer susceptibility associated with XRCC3 haplotypes, [15][16][17][18][19][20][21][22] whose allelic combination may serve as better makers for unknown functional variants than any single nucleotide polymorphism (SNP). Still, to date, and none of studies on XRCC3 haplotypes examined glioma risk.…”