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Carcinogenesis Advance Access originally published online on November 28, 2005
Carcinogenesis 2006 27(4):766-771; doi:10.1093/carcin/bgi295
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Joint effects of single nucleotide polymorphisms in P53BP1 and p53 on breast cancer risk in a Chinese population

Hongxia Ma 1, 2, {dagger}, Zhibin Hu 1, 2, {dagger}, Xiangjun Zhai 2, Shui Wang 3, Xuechen Wang 4, Jianwei Qin 5, Wenseng Chen 2, Guangfu Jin 1, 2, Jiyong Liu 2, Jun Gao 2, Xinru Wang 1, 2, *, Qingyi Wei 6 and Hongbing Shen 1, 2, *

1 Laboratory of Reproductive Medicine, 2 Department of Epidemiology and Biostatistics, Nanjing Medical University, 3 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 4 Department of General Surgery, Nanjing Gulou Hospital, 5 Department of General Surgery, Jiangsu Cancer Hospital, Nanjing 210009, China and 6 Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

* To whom correspondence should be addressed at Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, 140 Hanzhong Road, Nanjing 210029, China. Tel/Fax:+86 25 868 62756; Email: hbshen{at}njmu.edu.cn; xrwang{at}njmu.edu.cn


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
p53-binding protein 1 (P53BP1), a central transducer of DNA-damage signals to p53, is required for both intra-S-phase and G2-M checkpoints, suggesting that these two proteins may work together in the p53-mediated transcriptional activation and DNA damage-repair signaling pathways. Because the p53-binding region of 53BP1 maps to the C-terminal BRCT domains, which are homologous to those found in the breast cancer protein BRCA1, we hypothesized that genetic variation in P53BP1 and p53 may contribute to breast cancer predisposition. To test this hypothesis, we simultaneously genotyped single nucleotide polymorphisms of T-885G, Glu353Asp, and Gln1136Lys in P53BP1 and Arg72Pro in p53 in a case–control study of 404 breast cancer cases and 472 cancer-free controls. We found that the P53BP1 variant genotypes (alleles) of T-885G and Gln1136Lys were associated with a significantly increased risk of breast cancer among p53 Pro/Pro carriers (OR = 2.36, 95% CI 1.16–4.83 for –885TG/GG; OR = 2.24, 95% CI 1.15–4.37 for 1136Gln/Lys + Lys/Lys and OR = 2.82, 95% CI 1.15–6.94 for >4 variant alleles of these 3 loci). In addition, the variant genotypes of above 3 loci of P53BP1 were significantly associated with elevated risk of progesterone receptor (PR) negative breast cancer, and the T-885G and Gln1136Lys with estrogen receptor (ER) negative breast cancer. Furthermore, we found a significant gene-gene interaction between P53BP1 Gln1136Lys and p53 Arg72Pro variants in relation to breast cancer, and the OR of interaction for the presence of both P53BP1 1136Gln/Lys + Lys/Lys and p53 72Arg/Pro + Pro/Pro genotypes was 1.93 (95% CI 1.06–3.52) (P = 0.031 for interaction). These findings indicate that the SNPs in P53BP1 and p53 jointly contribute to breast cancer risk, particularly ER (–) or PR (–) breast cancer, and the p53 Arg72Pro polymorphism may serve as a risk modifier. Further functional studies are needed to confirm our findings.

Abbreviations: ER, estrogen receptor; LD, linkage disequilibrium; PR, progesterone receptor; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; BMI, body mass index


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The tumor suppressor protein, p53, is a principal mediator of multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle regulation, cell senescence and apoptosis. Somatic mutations inactivating the p53 gene are found in at least half of all human tumors, including breast cancer (1). Besides the acquired mutations, functional polymorphisms in p53 are among the most frequently studied cancer predisposing factors. Notably, an Arg72Pro variant resides in a proline-rich region of p53 is essential for p53-mediated apoptosis (2,3), and there appears to be sound biological evidence for functional differences between the Arg and Pro alleles (4–6).

The p53-binding protein 1 (P53BP1), a conserved nuclear protein, interacts with the DNA-binding core domain of the tumor suppressor p53 and enhances p53-mediated transcriptional activation (7,8). The p53-binding region of 53BP1 maps to the C-terminal BRCT domains, which are homologous to those found in the breast cancer protein, BRCA1. The interaction region of P53BP1, BRCT (BRCA1 C-terminus) repeats, was also found in proteins involved in DNA damage-signaling pathways (9–12), suggesting a more direct role of P53BP1 in the cellular response to DNA damage (13–16). Recently, studies suggested that P53BP1 is a positive regulator of the BRCA1 promoter (17) and a key transducer of the DNA damage checkpoint signal (18) and that it constitutively plays an important role in the etiology of human cancers (19). In animal models, P53BP1-deficient mice exhibit growth retardation, high radiation sensitivity and tumor development—features that are indicative of a defective DNA damage response (20,21).

Several genetic polymorphisms were recently identified in the coding and promoter regions of P53BP1 (http://egp.gs.washington.edu), including two non-synonymous single nucleotide polymorphisms (SNPs) Glu353Asp or 1236C->G (rs560191) and Gln1136Lys or 3583A->C (rs2602141) and a T->G transition at nucleotide –885 (rs1869258). Although there is no published report on any functional relevance of these three polymorphisms, it is biological plausible that sequence variation in the promoter and coding region of P53BP1 might affect its promoter transcription and thus the checkpoint response pathways responsible for DNA repair, leading to susceptibility to cancers.

In this case–control study of breast cancer, we hypothesized that common variants of P53BP1 and p53 and their joint effects are associated with risk of breast cancer. We therefore performed genotyping analyses for SNPs of T-885G, Glu353Asp and Gln1136Lys in P53BP1, and Arg72Pro in p53 in 404 breast cancer cases and 472 cancer-free controls frequency-matched to the cases on age (±5 years) and residential area.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population
A total of 404 breast cancer patients were consecutively recruited from the Departments of Breast Surgery of Cancer Hospital of Jiangsu Province (Nanjing), the First Affiliated Hospital of Nanjing Medical University, and the Nanjing Gulou Hospital, Jiangsu province, China, between January 2004 and May 2005. All subjects were genetically unrelated, ethnic Han Chinese women from Nanjing City and surrounding regions served by these hospitals and were all histopathologically diagnosed with incident breast adenocarcinoma (392 invasive and 12 in situ). The exclusion criteria included previous cancer, any metastasized cancer, and previous radiotherapy or chemotherapy. A total of 472 cancer-free controls, frequency-matched to the cases on age (according to cases' age groups by every 5 years) and residential area (the proportion of the cases by urban or rural areas), were randomly selected from a pool of 10 500 individuals participated in a community-based screening program for non-infectious diseases conducted in Jiangsu province during the same time period as the cases were recruited. After informed consent was obtained, each subject was personally interviewed face-to-face by trained interviewers using a pre-tested questionnaire to obtain information on demographic data, menstrual and reproductive history, lifestyles, environmental exposure and family history of cancer in first degree relatives (parents, siblings or children). After interview, a 5 ml venous blood sample was collected from each subject. The study was approved by the Ethics Committee (equivalent to institutional review board) of Nanjing Medical University.

Genotyping methods
Genomic DNA was extracted from leukocyte pellets by proteinase K digestion and followed by phenol-chloroform extraction and ethanol precipitation. The genotyping assay for the p53 codon 72 polymorphism was described previously (22). Briefly, we used a pair of primers of 5'-ATCTACAGTCCCCCTTGCCG-3' (sense) and 5'-GCAACTGACCGTGCAAGTCA-3' (antisense) to generate a 296 bp PCR product and then digested by restriction enzymes of BstUI (New England BioLabs, Beverly, MA) (Table I). The SNPs of T-885G, Glu353Asp and Gln1136Lys of P53BP1 were detected using a primer-introduced restriction analysis (PIRA)-PCR assay (23). For T-885G, the sense-primer was introduced a mismatched C to replace A at –2 bp from the polymorphic site to create a MspI restriction site. Similarly, the sense-primers were introduced a mismatched T to replace G and a mismatched G to replace A at –2 or –3 bp from the polymorphic sites to create a RsaI and a BclI restriction sites for Glu353Asp and Gln1136Lys, respectively (Table I). These three fragments were then digested, respectively, by MspI, RsaI and BclI (New England BioLabs) and separated on a 3% agarose gel (Table I).


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  		Table I. Primary information on genotyping assay of p53 Arg72Pro and P53BP1 T-885G, Glu353Asp and Gln1136Lys

 
Genotyping was performed without knowing the subjects' case and control status and approximately equal number of the cases and the controls were assayed in each 96-well PCR plate with a positive control of a DNA sample with known heterozygous genotype. If a consensus on the tested genotype was not reached, two research assistants independently performed the repeated assays to achieve 100% concordance. In addition, ~10% of the samples (40 cases and 50 controls) were randomly selected for repeated assays and the results were all consistent. In order to further validate the genotyping assay, three PCR products of each locus of the P53BP1 with different genotypes were confirmed by direct sequencing using an automated sequencer (ABI model 377, Perkin-Elmer Applied Biosystems, Wellesley, MA).

Statistical analyses
Differences in demographic characteristics, selected variables and frequencies of the genotypes and haplotypes of p53 and P53BP1 polymorphisms between the cases and controls were evaluated using the {chi}2-test (for categorical variables) and Student's t-test (for continuous variables). The associations between p53 and P53BP1 genotypes and the risk of breast cancer were estimated by computing the odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analyses with adjustments for age, age at menarche, body mass index (BMI), menopausal status and family history of cancer. Hardy-Weinberg equilibrium was tested by a goodness-of-fit {chi}2-test to compare the observed genotype frequencies to the expected ones among the control subjects. Linkage disequilibrium (LD) between these three loci of P53BP1 was estimated using the exponential histogram (EH) algorithm available online (http://linkage.rockefeller/edu/soft). We used the PHASE 2.1 program (24) to infer P53BP1 haplotypes based on the known genotypes for each subject and tested the difference of the distribution of all the haplotypes between the cases and the controls by using the {chi}2-test. The ORs (95% CIs) of haplotypes were estimated using the logistic regression analyses. All the statistical analyses were performed with Statistical Analysis System software (v.8.0e; SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The selected characteristics of the 404 breast cancer cases and 472 cancer-free controls are summarized in Table II. A lower age at menarche, at menopause and a higher age at having first live birth might be independent risk factors for breast cancer. There were 110 (27.2%) cases and 94 (19.9%) controls who reported a family history of cancer, which was associated with a 51% significantly increased breast cancer risk (OR = 1.51; 95% CI 1.10–2.06).


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  		Table II. Distributions of select variables in breast cancer cases andcancer-free controls

 
The genotype distributions of p53 Arg72Pro and P53BP1 T-885G, Glu353Asp and Gln1136Lys in the cases and the controls are shown in Table III. The observed genotype frequencies for these four polymorphisms were all in Hardy–Weinberg equilibrium in the controls (P = 0.291, 0.190, 0.914 and 0.571 for p53 Arg72Pro and P53BP1 T-885G, Glu353Asp and Gln1136Lys, respectively). In the single locus analyses, none of the four polymorphisms achieved significant difference in the genotype distributions between the cases and the controls (P = 0.277, 0.245, 0.747 and 0.187 for Arg72Pro of P53, T-885G, Glu353Asp and Gln1136Lys of P53BP1, respectively). Multivariate logistic regression analyses revealed that a non-significantly increased risk of breast cancer was associated with the variant genotypes of P53BP1 T-885G and Gln1136Lys [adjusted OR = 1.30 (95% CI 0.96–1.76) for –855TG, 1.31 (95% CI 0.88–1.96) for –855GG and 1.47 (95% CI 0.97–2.22) for 1136Lys/Lys], compared with their wild-type genotypes, respectively (Table III). In the subgroup analyses, we found that the variant genotypes of P53BP1 T-885G, Glu353Asp and Gln1136Lys were all associated with significantly increased risk of breast cancer with progesterone receptor (PR) negative [adjusted OR = 2.15 (95% CI 1.36–3.41) for –855TG/GG, 1.59 (95% CI 1.02–2.47) for 353Glu/Asp + Asp/Asp and 2.01 (95% CI 1.30–3.10) for 1136Gln/Lys + Lys/Lys, respectively]. In addition, the variant homozygotes of P53BP1 –885GG and 1136Lys/Lys were associated with significantly increased risk of breast cancer with estrogen receptor (ER) negative [adjusted OR = 2.04 (95% CI 1.16–3.57) for –855GG and 2.28 (95% CI 1.30–3.98) for 1136Lys/Lys, respectively] (Table III). However, the risk of breast cancer associated with P53BP1 polymorphisms was similar in different subgroups by grade and stage of breast cancer (data not shown).


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  		Table III. Logistic regression analysis of associations between p53 and P53BP1 polymorphisms and risk of breast cancer

 
In order to evaluate the joint effect of P53BP1 polymorphisms and p53Arg72Pro genotypes on breast cancer risk, we performed stratification analyses by p53Arg72Pro genotypes. As shown in Table IV, we found that the variant genotypes of T-885G and Gln1136Lys were associated with a significantly increased risk of breast cancer among carriers with p53 Pro72Pro [adjusted OR (95% CI) = 2.36 (1.13–4.93) for –855TG; 2.39 (0.90–6.31) for –855GG; and 2.36 (1.16–4.83) for –855TG/GG, respectively; and adjusted OR (95% CI) = 2.00 (1.01–3.98) for 1136Gln/Lys, 3.01 (1.16–7.85) for 1136Lys/Lys and 2.24 (1.15–4.37) for 1136 Gln/Lys + Lys/Lys, respectively]. We then examined the combined effect of these three P53BP1 loci on breast cancer risk. Again, in the p53Pro/Pro carriers, we found a significantly increased risk of breast cancer associated with the combined P53BP1 genotypes containing ‘3 variant alleles’ (adjusted OR = 2.10; 95% CI 1.05–4.21) and ‘≥4 variant alleles’ (adjusted OR = 2.82; 95% CI 1.15–6.94) in a dose–response manner (Trend test: P = 0.034), compared with the combined 53BP1 genotypes containing ‘0–2 variant alleles’ (Table IV).


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  		Table IV. Stratified analyses between P53BP1 polymorphisms and breast cancer risk by p53 Arg72Pro genotypes

 
In the LD analysis, we found that all three variants of P53BP1 were in high LD with each other (D' = 0.832, R2 = 0.645 for T-885G and Glu353Asp; D' = 0.899, R2 = 0.641 for Glu353Asp and Gln1136Lys; D' = 0.869, R2 = 0.640 for T-885G and Gln1136Lys). Eight haplotypes were derived from the observed genotypes of these three P53BP1 polymorphisms (Table V). In p53Pro/Pro carriers, the distributions of P53BP1 haplotypes were significantly different between cases and controls (P = 0.019), and the GGC haplotype harboring three P53BP1variant alleles was more common in cases than in controls, which was associated with a 1.73-fold increased risk of breast cancer (95% CI 1.09–2.74), compared with the most common haplotype TCA (Table V).


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  		Table V. Frequencies of inferred haplotypes of P53BP1among p53 Pro/Pro carriers based on the observed genotypes in breast cancer cases andcancer-free controls

 
Furthermore, we found a significant gene-gene interaction between P53BP1 Gln1136Lys and p53Arg72Pro variants in relation to risk of breast cancer, and the adjusted OR of interaction for the presence of both P53BP1 1136Lys/Lys + Gln/Lys and p5372Arg/Pro + Pro/Pro genotypes was 1.93 (95% CI 1.06–3.52) (P = 0.031 for interaction test). However, we did not find any statistical evidence for an interaction between P53BP1 variant genotypes and other risk factors (e.g. family history of cancer, menopausal status and age at menarche) in the risk of breast cancer (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In this hospital-based case–control study, we investigated the associations of three SNPs of P53BP1 and the Arg72Pro SNP of p53 with risk of breast cancer in a Chinese population. We found that the variant genotypes (alleles) of P53BP1 T-885G, P53BP1 Gln1136Lys, and the haplotypes of three SNPs of P53BP1 were associated with a significantly increased risk of breast cancer among p53 Pro/Pro carriers. In addition, the variant genotypes of P53BP1 T-885G, Glu353Asp and Gln1136Lys were significantly associated with elevated risk of PR(–) breast cancer, and the T-885G and Gln1136Lys with ER(–) breast cancer. Furthermore, we found a significant gene-gene interaction between P53BP1 Gln1136Lys and p53 Arg72Pro variants in relation to risk of breast cancer. These findings indicate that the SNPs in P53BP1 and p53 may jointly contribute to breast cancer risk, particularly for those with PR(–) or ER(–) breast cancer, and the p53 Arg72Pro polymorphism may serve as a risk modifier.

The p53 Arg72Pro polymorphism was well characterized in both functional analyses and association studies. It has been shown that cells harboring the Arg variant appear to be more susceptible to the degradation induced by human papillomavirus E6 protein (4) but more efficient in inducing apoptosis (5) and suppressing cellular transformation (25). Marin et al. (6) reported that the Arg allele was preferentially mutated and retained in squamous cell tumors arising in Arg/Pro germline heterozygotes and concluded that the codon 72 polymorphic residue within p53 affects mutant protein behavior. To investigate the impact of the p53 Arg72Pro variant on the tumor development, molecular epidemiological studies were conducted intensively for almost all major cancer types, including cervical (26,27), lung (28,29), colorectal (30), gastric (22), bladder cancer (31) and others (32,33). However, the results from these association studies remain inconsistent rather than conclusive. As for breast cancer, Suspitsin et al. (34) reported a borderline significantly increased risk associated with the p53 72Pro allele carriers based on a meta-analysis of seven case–control studies. Contradictorily, the p53 72Arg allele was identified, recently, as a significant risk predictor for both sporadic and familial breast cancer (35,36). In this study of a Chinese population, we also observed a risk effect of 72Arg allele on sporadic breast cancer; however, this association was not statistically significant.

To date, there is only one study that investigated the role of P53BP1 variants in cancer susceptibility. In a case-control study including 353 breast cancer patients and 960 controls in a German population, Frank et al. (37) investigated three coding SNPs of D353E, G412S and K1136Q of P53BP1 and one very rare P53BP1 6 bp deletion (1347_1352delTATCCC) and reported overall no association between P53BP1 variants and breast cancer risk. However, p53 Arg72Pro variant was not included in that study. Considering the reported frequencies of the above variants, we selected two coding SNPs of D353E and K1136Q, and one novel promoter variant T-885G in 53BP1 in our Chinese study. In addition, because p53 and P53BP1 work together in the DNA damage-signaling pathway, we simultaneously genotyped the p53 Arg72Pro polymorphism to evaluate the potential interaction between these two genes. Although similar to the findings of Frank et al. (37) we did not find any significant main effects for both p53 and P53BP1 variants, we did observe a significant interaction between P53BP1 Gln1136Lys and p53 Arg72Pro variants in relation to breast cancer risk. It is biologically plausible that the P53BP1 Gln1136Lys itself or its surrounding region might be a biomarker to play a role in interacting with binding to p53 protein (38). Obviously, the biological evidence for this gene–gene interaction needs further in-depth investigations.

The frequencies of genetic polymorphisms often vary between ethnic groups. In the German case–control study on P53BP1 polymorphisms, the Glu353Asp genotypes were 47.6% for CC, 42.5% for CG and 9.9% for GG in controls (37), which was significantly different from those in our Chinese population (30.9% for CC, 50.9% for CG and 18.2% for GG (P < 0.0001). Similarly, the genotype frequencies for Gln1136Lys were 47.8% for AA, 42.2% for AC and 10.0% for CC in German people (37), which were also different from those in the Chinese population (37.4% for AA, 50.0% for AC and 12.6% for CC) (P = 0.0011). These ethnic differences may generate different results in case-control studies, which may need further validation by prospective studies.

In this case–control study, several limitations need to be addressed. First, as we enrolled the patients from hospitals and random controls from the population, inherent selection bias cannot be completely excluded. However, we applied a rigorous epidemiological design in selecting study subjects and used further statistical adjustments to minimize potential biases. Second, the moderate sample size limited the statistical power of our study and large well-designed studies are warranted to confirm our findings, particularly the gene–gene and gene–environment interactions. Third, we only genotyped p53 codon 72 polymorphism and did not analyze other potentially functional variants. Recent studies reported that p53 codon 72 was in strong LD with other two loci of the gene (a 16 bp duplication in intron 3 and a A->G in intron 6) (28,30) and P53PIN3 polymorphism was associated with a high population attributable risk for cancer (30), indicating the important role in carcinogenesis in addition to p53 Arg72Pro. Further studies with multiple SNPs of the genes in the same pathway may provide more valuable information in terms of the gene-gene interactions. Finally, our study lacked the related phenotypic and functional assays (i.e. apoptosis assay and DNA repair capacity), which limited our inquiry into the functional consequence of these variants. However, such association studies with significant findings may lead to further functional studies that will elucidate the underlying mechanisms of breast cancer development associated with these genetic variants.

In conclusion, our study demonstrated, for the first time, that P53BP1 and p53 polymorphisms may jointly contribute to risk of breast cancer in a Chinese population. Validation of these findings with functional evaluation and larger studies with more rigorous study designs of other ethnic populations are needed.


   Notes
 
{dagger} These authors contributed equally to this work. Back


   Acknowledgments
 
This work was supported in part by the National Key Basic Research Program, Grant no. 2002CB512908; Jiangsu Natural Science Foundation, Grant no. BK2004145; and Post-doctoral Science Foundation of China, Grant no. 2004035218.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received August 10, 2005; revised October 24, 2005; accepted November 15, 2005.


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