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Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1306-1310, July 2006
© 2006 American Association for Cancer Research

A Role for XRCC4 in Age at Diagnosis and Breast Cancer Risk

Kristina Allen-Brady1, Lisa A. Cannon-Albright1, Susan L. Neuhausen2 and Nicola J. Camp1

1 Genetic Epidemiology, Department of Medical Informatics, University of Utah, Salt Lake City, Utah and 2 Division of Epidemiology, Department of Medicine, University of California Irvine, Irvine, California

Requests for reprints: Kristina Allen-Brady, Genetic Epidemiology, Department of Medical Informatics, University of Utah, 391 Chipeta Way, Suite D, Salt Lake City, Utah 84108. Phone: 801-581-5070. E-mail: kristina.allen{at}hsc.utah.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D' = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1306–10)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although repair of double-strand DNA breaks (DSB) is part of normal physiologic processes, including meiotic recombination and immunoglobulin gene rearrangement [V(D)J recombination], DSB may also arise through exposure to DNA-damaging agents (1-3). Unrepaired or improperly repaired DSB may result in cell death or through genomic rearrangements and destabilization of the genome, eventually result in cancer (4-6).

In eukaryotic cells, DSB are repaired by two different pathways: homologous recombination and nonhomologous end joining (NHEJ; refs. 7, 8). Homologous recombination, in brief, requires a homologous template on the sister chromatid to fix a break, whereas NHEJ, considered more error prone, reseals the two free DNA ends without the need of a template (9-11). DNA DSB repair pathways are of etiologic importance during tumorigenesis, particularly breast cancer tumorigenesis. Several high-penetrant mutations in DSB repair genes have been found to be involved in breast cancer, including BRCA1, BRCA2, and ATM (12). As high-penetrant mutations explain only a small percentage of breast cancer, recent efforts have focused on common variants in DNA repair pathways, and nominally, significant results have been observed (13-17). Unfortunately, most of these studies have focused on a limited number of single nucleotide polymorphisms (SNP) without regard to whether these common variants capture all or most of the underlying genetic variation across the gene. A more thorough approach is to study tagging SNPs (tSNP), which are specifically selected to represent the majority of the underlying genetic variability (18).

As BRCA1 and BRCA2 play an important role in homologous recombination repair and strongly predispose to cancer, much emphasis has been placed on the homologous recombination pathway to find additional breast cancer susceptibility genes (19, 20). Recent evidence, however, suggests that BRCA1 may also play a role in the NHEJ pathway (21, 22). Animal studies have shown that BRCA1-deficient mouse embryonic fibroblasts were significantly more likely to have reduced NHEJ activity (23, 24). Bau et al. found that breast cancer risk was jointly associated with a higher number of high-risk genotypes in NHEJ genes and the BRCA1 Glu1038Gly polymorphism (21). Bau et al. further found that the precision of NHEJ repair was higher in BRCA10-expressing cell lines (MCF-7 cells) than those with defective BRCA1 expression (HCC1937). These studies suggest that the homologous recombination and NHEJ pathways might not be as distinct as was thought previously.

Because of the potential contribution of the NHEJ pathway to breast cancer and the need for further study of genes in this pathway, the aim of the current study was to determine whether common genetic variants in one of the NHEJ pathway genes, XRCC4, are associated with breast cancer. Here, we report the genotypic and haplotypic association of XRCC4 with breast cancer risk and age at diagnosis in high-risk Utah breast cancer families. Association studies using familial breast cancer cases can increase the power to detect rare low-penetrance variants over that of unselected breast cancer cases (25).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Subjects for this study were selected from 139 high-risk Utah breast cancer pedigrees of northern European descent. These families were originally selected and considered high risk because their rates of breast cancer exceeded the population rate of breast cancer determined using the Utah Population Database, a database linking genealogy data to the Utah Cancer Registry (26). Breast cancer cases were selected to have a low probability of being attributable to BRCA1/2 mutations because either the breast cancer case themselves or other family members tested negative for a BRCA1/2 mutation (97.2% of cases) or the number and constellation of breast cancer cases present and/or ages of diagnosis of breast cancer in the family made the breast cancer unlikely to be due to BRCA1/2 mutations (2.8% of cases). Breast cancer case status and age at diagnosis were obtained from either medical records or Utah Cancer Registry. All breast cancer cases in the state of Utah must be reported to the Utah Cancer Registry by law; thus, the Utah Cancer Registry is a reliable information source.

We selected nuclear families conducive for transmission/disequilibrium testing, composed of parent-affected female offspring trios (n = 39) and, when parental blood was unavailable, female sibships (n = 167), containing at least one affected and one unaffected sibling from the breast cancer pedigree resource described above. We supplemented these nuclear families by adding the remaining female non-BRCA1/2 breast cancer cases from the breast cancer pedigree resource who had blood available (n = 236), and each was matched to a control subject (n = 236). Matching of these additional cases and controls was based on birth year (within 5 years), female gender, and age at diagnosis, such that the control was cancer-free at the age the case was diagnosed. The matched controls were also chosen from the breast cancer pedigree resource and selected to be as distantly related to any other matched case and control as possible to maximize power, and as old as possible, while still matching by birth-cohort, to ensure that they were less likely to become a case. The total sample size contained all non-BRCA1/2 breast cancer cases with samples available (464 cases and 576 controls). These subjects were part of pedigrees, which ranged in size from selecting a single individual from a family to 1,195 individuals, although typically, only individuals at the bottom of each pedigree had DNA available. All subjects studied gave informed consent. This study was approved by the University of Utah Institutional Review Board.

tSNP Determination and Genotyping of Subjects
We characterized previously the linkage disequilibrium (LD) structure and haplotype architecture and identified four tSNPs that captured 97.2% of the intragenic variation across XRCC4 (27). In brief, we evaluated 21 SNPs across XRCC4 at a resolution of 1 SNP/13,198 bp using 94 unrelated individuals. Using a principle components analysis method (28), we observed four LD groups leading to the identification of four tSNPs, one for each group. The four tSNPs used for this study were rs1478485, rs13180316, rs963248, and rs1056503, which we will refer to as X1, X2, X3, and X4, respectively.

These four tSNPs were genotyped on the entire study population (N = 1,040), using the same genotyping procedure as that used for the tSNP determination (see ref. 27 for genotyping details). For quality control, six individuals were duplicated across all plates. Analysis required that the quality control samples across plates have matching genotype assignments. Where possible, Mendelian inheritance was verified; samples with inheritance incompatibilities were either regenotyped and/or set to missing if they could not be resolved.

Statistical Analysis
As all subjects were selected from 139 pedigrees and many of them are related, we corrected for the genetic dependence between them. Without correction, an underestimate of the variance and an increase in the type I error rate may result. We used PedGenie (29, 30), a freely available tool developed by our group, to do association testing between genetic markers and qualitative and quantitative traits in pedigree data of any size or structure. PedGenie accounts for the relatedness of individuals using a Monte Carlo approach to significance testing, whereby an empirical null distribution is generated and used to determine the significance of an observed result. PedGenie performs classic tests of association and transmission disequilibrium for both single locus analyses and phased haplotype data.

Association tests were done using all subjects (N = 1,040), and transmission tests were restricted to the subsample with relevant structure (39 trios and 167 sibships). In all analyses, the base variant with the minor allele was considered the allele of interest (see Table 3). For age at diagnosis analyses, we restricted the sample to affected breast cancer cases only. We examined each tSNP independently and in multilocus haplotypes. For single locus analyses, the allele frequency estimation method "GeneCounter" in PedGenie was used, such that simulations are based on statistically inferring allele frequencies for founders using maximum likelihood estimation. For haplotype analyses, PedGenie requires haplotype frequencies and recombination fractions between loci. Haplotype frequencies were determined from a subset of unrelated individuals (n = 94) using an expectation-maximization algorithm (31). The recombination fractions between each of the four tSNPs were set to zero, as the distances between the SNPs were small (range, ~74-115 kb).


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  		Table 3. XRCC4 haplotypes

 
Haplotype testing requires phase information for all genotyped subjects. Although several pedigree-based haplotype methods are beginning to be developed (32-37), none is able to provide individual haplotype assignment on large pedigrees with large amounts of missing data, assuming LD between multiple markers (see also ref. 38). We inferred haplotype phase information for all genotyped subjects using the expectation-maximization algorithm with a probability of assignment ≥80%, ignoring relationships (31). With an assumption of zero recombination, this is unbiased (39). All assigned haplotypes were checked for segregation within families wherever possible. Haplotypes that were incompatible within the family were set to zero.

For all analyses, the empirical null distribution and Ps from PedGenie were determined from a sample size of 2,000 null configurations. To account for multiple testing and realizing that all tests done and the loci considered were not independent, we report all nominal findings (P < 0.05) as interesting and have considered a probability threshold of P ≤ 0.005 as significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Characteristics of our breast cancer resource are described in Table 1 . Table 2 shows the results for each of the four tSNPs analyzed separately. Two tSNPs achieved significance for age at diagnosis (X1 and X2). A significant association was found for breast cancer cases homozygous for allele A at X1 (recessive model) resulting in a later age at diagnosis (mean, 59.1 years; P = 0.003) compared with homozyogote and wild-type (WT) individuals (mean, 54.6 years). For X2, carriage of allele A (dominant model; P = 0.01) was associated with a significantly earlier age at diagnosis of cancer (mean, 53.4 years; P = 0.004) compared with WT individuals (mean, 57.0 years), although this result was driven solely by the heterozygote carriers for allele A. For breast cancer risk, carriage of allele A at X2 also approached nominal significance (P = 0.08).


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  		Table 1. Characteristics of breast cancer cohorts

 

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  		Table 2. Association of XRCC4 tSNPs with breast cancer risk and age at diagnosis (cases only)

 
The trio–transmission/disequilibrium test (TDT) results were nominally significant for overtransmission of allele A at X1 to breast cancer cases (TDT, 5.44; P = 0.02). All other trio, sib, and combined trio-sib TDT analyses, as well as the combined trio-sib quantitative TDT statistics, were nonsignificant for all other single locus analyses.

Table 3 lists all of the phased haplotypes and their frequencies that were observed in the subset of 94 unrelated individuals using the four XRCC4 tSNPs. There were 10 haplotypes ranging in frequency from 0.4% to 39.7%.

As X1 and X2 showed significance for single locus tests and as they are in strong relative LD (D' = 0.99) accounting for allele frequencies, we did two-locus tSNP haplotype analyses across these two loci. Only three haplotypes were observed, G-G, G-A, and A-G, and association results considering these three haplotypes are shown in Table 4 . As expected, interesting results were found for age at diagnosis for a recessive model of haplotype A-G (P = 0.007) and carriage of haplotype G-A (P = 0.011), with the signal coming from those heterozygous for G-A (P = 0.005). However, these results were less significant than that observed for the individual tSNPs (see above). For breast cancer risk, nominally significant results were observed for homozygosity of haplotype G-G (P = 0.014) and carriage of haplotype G-A (P = 0.033).


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  		Table 4. Two-locus XRCC4 tSNP haplotype tests of association with breast cancer risk and age at diagnosis (cases only)

 
The TDT results for the two-locus haplotypes were nominally significant for overtransmission of the A-G haplotype using the trio TDT statistic (TDT, 4.84; P = 0.039). All other trio, sib, and combined trio-sib TDT analyses, as well as the quantitative combined trio-sib TDT, for the G-G, G-A, and A-G haplotypes were nonsignificant.

For breast cancer age at diagnosis, haplotypes beginning with A-G and G-A were most interesting. We analyzed four-locus extensions of these, and the corresponding association results are shown in Table 5 . For four-locus haplotypes beginning with A-G, carriage of A-G-T-G (H5) resulted in a significantly (P = 0.001) later age at diagnosis of breast cancer (mean, 67.17 years) compared with all other diploid combinations of haplotypes (mean, 55.27 years). The other three haplotypes beginning with A-G (H1, H6, and H10) indicated no association. Similarly, when we considered the four-locus extension to G-A, only G-A-T-T (H2) indicated association (P = 0.0085) with an effect toward earlier breast cancer diagnosis (mean, 54.04 years) compared with all other haplotype combinations (mean, 56.63 years). Both results are not only more significant than the single- and two-locus results containing the relevant variants but also the mean diagnosis ages are more extreme. For these age at diagnosis results, the extension to four-locus haplotypes seems to better extract the association evidence.


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  		Table 5. Association of selected four-locus XRCC4 haplotypes and age at diagnosis of breast cancer

 
For breast cancer risk, haplotypes beginning with G-A and G-G were most interesting. We analyzed four-locus extensions of G-A and G-G, and corresponding association results are presented in Table 6 . There were only two 4-locus haplotypes extending from G-A and both showed nominally significant association with breast cancer risk (G-A-T-T; P = 0.048 and G-A-T-G; P = 0.02), consistent with the two-locus findings for G-A. For the four 4-locus haplotypes extending from G-G, two had nominal (G-G-T-T; P = 0.022 and G-G-C-G; P = 0.019) and one had significant association with decreased risk (G-G-T-G; P = 0.003), consistent with the two-locus findings for G-G.


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  		Table 6. Association of selected four-locus XRCC4 haplotypes and breast cancer risk

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results suggest that variants in the DNA repair gene XRCC4 may be associated with breast cancer risk and the age at which breast cancer is diagnosed. Our findings are based on four tSNPs, selected to capture the majority of the underlying variance across the XRCC4 gene, and a sample of non-BRCA1/2 breast cancer cases from Utah high-risk pedigrees.

For breast cancer risk, we observed that haplotypes beginning with G-G were associated with protection against breast cancer, whereas haplotypes beginning with G-A were associated with increased risk of breast cancer. The increased or decreased risk of cancer was consistent in the majority of all four-locus haplotype extensions, with mostly nominal Ps and one significant P value observed. To determine if these findings represented two independent associations, we selected the most common haplotype (H1) in a diplotype state (H1-H1) as the reference group and repeated analyses. Despite a decrease in power due to the H1-H1 reference group having a substantially smaller sample size, these results remained consistent with our original findings. In particular, the results showed that haplotypes beginning with G-G maintained decreased risk even when the G-A haplotypes were not contained in the comparison group, and the G-A haplotypes maintained an increased risk even when the G-G haplotypes were not in the comparison group; hence suggesting two independent haplotype findings. The fact that the association signal is tagged equally well by two-locus tSNP haplotypes across X1 and X2 indicates that the underlying variant(s) is likely ancient, common in strong LD with X1 and X2, and that sufficient time has lapsed so that recombination has allowed for multiple haplotypes containing the risk variant(s).

For age at diagnosis, we observed an association for two specific four-locus tSNP haplotypes; one associated with later diagnosis [A-G-T-G (H5): mean, 67.17 years] and one associated with effect toward earlier diagnosis [G-A-T-T (H2): mean, 54.04 years]. These two 4-locus haplotypes explained all of the association seen for the two-locus haplotype analyses across X1 and X2, and consistent results were again observed by repeating analyses using the H1-H1 diplotype as the reference group, again suggesting two independent haplotype findings. To further investigate these results, we also stratified breast cancer cases by the mean age at diagnosis (i.e., 55.6 years) and examined the breast cancer risk associated with carriage of H2 and H5. In the cohort defined as earlier diagnosis (i.e., ≤55.6 years), carriage of H2 resulted in a significantly increased risk of breast cancer [odds ratio (OR), 1.64; 95% confidence interval (95% CI), 1.22-2.21; P = 0.001], consistent with our original results. In the cohort defined as later diagnosis (i.e., >55.6 years), carriage of H5 resulted in an increased risk of breast cancer (OR, 2.24; 95% CI, 1.23-4.10; P = 0.011), again consistent with our original results. As the putative underlying susceptibility variant(s) seems to be tagged better by four-locus tSNP haplotypes, this indicates that the variant(s) likely arose more recently, such that it is rarer and lies on more extended unique haplotypes.

The tSNPs used for this study were not selected as functional variants but rather as markers to capture the underlying variation across XRCC4. tSNP rs1478485 (X1) lies in the mRNA-untranslated region, tSNPs rs13180316 (X2) and rs963248 (X3) are both intronic, and tSNP rs1056503 (X4) results in a synonymous coding change. Therefore, there are no predicted effects for these individual polymorphisms on the protein sequence. It is possible that they may be involved in the expression or stability of the XRCC4 mRNA, in modification of splicing, but most likely in LD with causal variant(s).

Two previous studies have examined association of a limited number of SNPs in the XRCC4 gene and risk of breast cancer. Fu et al. found a SNP (rs2075685) in the XRCC4 gene to be significantly associated with breast cancer risk (OR, 0.583; P = 0.02) in a Taiwanese breast cancer case-control study (15). Lee et al. (16) tested rs1056503, which is our X4, in a Korean hospital-based case control study but did not find significance for carriage of the rare allele (OR, 1.04; 95% CI, 0.82-1.30), consistent with our findings for X4 when analyzed alone.

To investigate whether the significant SNP in the Fu et al. (15) study (rs2075685) was in LD with any of our XRCC4 tSNPs, we selected all genotypes from unrelated Han Chinese (CHB) subjects (n = 45), the most ethnically similar population to the Taiwanese population studied by Fu et al. (15), and unrelated parental genotype data from the Centre d'Etude du Polymorphisme Humaine Utah families (n = 60) found in HapMap (40). Two of our four tSNPs [rs13180316 (X2) and rs963248 (X3)] as well as rs2075685 were available for download. The relative pair-wise LD was high between rs2075685 and X2 (D' = 1.00) and moderate between rs2075685 and X3 (D' = 0.511) using CHB subjects, and using Centre d'Etude du Polymorphisme Humaine subjects, LD was moderate between rs2075685 and X2 (D' = 0.51) and high between rs2075685 and X3 (D' = 0.81). Hence, it is likely that both our study and the Fu et al. (15) study are detecting the same XRCC4 variant(s) that predisposes to breast cancer risk.

To the best of our knowledge, this is the first study to note a significant association between tSNP haplotypes in XRCC4 and age at diagnosis of breast cancer. Confirmation of these results in other populations is necessary. The risk haplotype for later age at diagnosis (and most likely the underlying causal variant) is fairly rare (frequency, 0.039; n = 12 cases in our population), whereas the opposite haplotype conferring an earlier age at diagnosis was more common (frequency, 0.214; n = 184 cases in our population); hence, the attributable risk to the breast cancer population could be considerable.

There are limitations of this study. Although the use of heritable breast cancer cases increases the power of association studies to detect low-penetrance variants (25), it is most advantageous to use independent hereditary breast cancer cases and unrelated controls (25, 41-45). In addition, although we used a more stringent significance threshold for these analyses, the true significance correction is difficult to determine due to correlation of individual variants and the haplotypes on which they reside. A potential bias may also be present in our analyses, as males from the trio sample were included in the complete cohort analyses. However, reanalyzing the data excluding males did not change our conclusions (data not shown). Finally, we did not sequence the XRCC4 gene to determine tSNPs, rather we tested selected SNPs commercially available at a resolution of 1 SNP/~10 kb. It will therefore be of interest to determine whether our results extend to larger cohorts, sporadic cases, and breast cancer attributable to BRCA1/2.

In conclusion, our results suggest that variants of the XRCC4 gene play an important role in both the development of breast cancer and in determining the age at diagnosis of hereditary breast cancer not attributable to BRCA1/2. Further studies involving larger cohorts of women and more extensive genotyping across XRCC4 are required to validate our findings and locate the underlying causal variants.


   Acknowledgments
 
We thank two anonymous reviewers for helpful suggestions and Kim Nguyen, Michael Hoffman, Helaman Escobar, and Michael Klein for their assistance in the laboratory.


   Footnotes
 
Grant support: National Library of Medicine grant T15 LM0724, Susan G. Komen Breast Cancer Foundation grant DISS0201521, and National Cancer Institute grant CA 098364.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/26/05; revised 4/22/06; accepted 5/12/06.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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