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Do MDM2 SNP309 and TP53 R72P Interact in Breast Cancer Susceptibility? A Large Pooled Series from the Breast Cancer Association Consortium

¹ Netherlands Cancer Institute, Amsterdam, the Netherlands; ² Departments of Gynaecology and Radiation Oncology, Hannover Medical School, Hannover, Germany; ³ Leiden University Medical Center, Leiden, the Netherlands; ⁴ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research; ⁵ Cancer Research UK Genetics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom; ⁶ The Institute of Cancer Research, Sutton, Surrey, United Kingdom; Departments of ⁷ Obstetrics and Gynecology and ⁸ Oncology, Helsinki University Central Hospital, Helsinki, Finland; and ⁹ Strangeway's Research Laboratory, Cambridge, United Kingdom

Requests for reprints: Laura J. Van't Veer, Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Phone: 31-20-512-2754; E-mail: l.vt.veer{at}nki.nl.

	Abstract

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Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81–1.23]. Estimated ORs were 1.01 (95% CI, 0.93–1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91–1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor–positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study. [Cancer Res 2007;67(19):9584–90]

	Introduction

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Highly penetrant variant alleles of BRCA1 and BRCA2 explain about 2% to 4% of breast cancers in the general female population (1). The remainder of breast cancer susceptibility is likely to be due to multiple susceptibility alleles conferring low to moderate risks (1–4). Rare variants in ATM, CHEK2 (1, 5, 6), BRIP1 (7), and PALB2 (8) confer an 2-fold risk of breast cancer, and the coding variant CASP8 D302H is associated with a reduced risk of breast cancer (9). These variants, however, only account for a minority of the hereditary component of breast cancer. Association studies in large series of patients, such as the Breast Cancer Association Consortium (BCAC; refs. 3, 9), have been able to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Genes that have a function in DNA damage response, such as TP53 and its key regulator MDM2 (10), are strong candidates for breast cancer susceptibility genes.

MDM2 is overexpressed in various cancers and there are indications that this leads to a worse prognosis at least in some cancers (11). One polymorphism in the promoter region of MDM2, SNP309 (T>G change at nucleotide 309 in the first intron; rs2279744), has been reported to be associated with earlier (>10 years) onset of breast cancer in Li-Fraumeni patients (12–14) as well as with earlier onset of sporadic soft tissue sarcoma (12) and (female) colon cancer (15, 16) and with risk for gastric carcinoma (17). SNP309 leads to increased expression of the Mdm2 mRNA and attenuated function of the p53 protein (12). To date, however, no evidence for an association between SNP309 and breast cancer outside of Li-Fraumeni patients has been found. One large study in African-Americans and Whites in North Carolina (n = 2,037; ref. 18) and several small studies in Chinese (n = 366; ref. 19), German non-BRCA1/2 familial (n = 549; ref. 20), British (n = 351; ref. 21), Baltimore (n = 293; ref. 22), and Turkish (n = 223; ref. 23) breast cancer cases found no evidence for an increased risk of breast cancer. However, it has been suggested that SNP309 could alter effects of hormones such as estrogen on the MDM2 promoter in the context of breast tumorigenesis (16, 24, 25) and that SNP309 may be specifically associated with the early age at onset in estrogen receptor–positive tumors (25).

TP53 is frequently somatically mutated in breast tumors, whereas germ-line mutations in TP53, which are present in <1% of the general breast cancer population (26), are the major cause of the Li-Fraumeni syndrome (14). A coding variant of TP53, R72P (G>C change at nucleotide 215 in codon 72 resulting in a substitution of proline for arginine in the protein sequence; rs1042522), has been associated with an increased risk for human papillomavirus–related cervical cancer and several other cancer types in some studies (lung, prostate, ovary, and skin), but the results have been inconsistent (26, 27). Earlier age of onset for colorectal cancer in TP53 R72P variant carriers was reported in a small study of hereditary nonpolyposis colorectal cancer patients (28). A pooled analysis by the BCAC found no evidence of an increased risk of breast cancer associated with R72P (3). However, the TP53 Pro variant has been reported to lead to worse survival in breast cancer patients (29) and other cancers (27), which may be related to its different apoptotic and DNA repair potential (30, 31). In addition, there is some evidence that it may be associated with earlier onset of breast cancer in BRCA1 or BRCA2 mutation carriers (29, 32, 33).

Earlier, we confirmed the finding of Bond et al. (12) that MDM2 SNP309 is associated with earlier age at onset of breast cancer in Li-Fraumeni patients with a TP53 germ-line mutation (14). However, we found no associations with age at onset in cancer patients with a Li-Fraumeni–like family history but no TP53 mutation (14). This raises the possibility that, although there may be no effect of variant alleles of TP53 and MDM2 on their own, in combination they may lead to an increased risk of cancer or earlier age at onset. A combination of variant alleles in TP53 R72P (Pro/Pro) and MDM2 SNP309 (GG and TG) was reported to modify the age of onset in Li-Fraumeni patients (13), and a suggestion for such an effect was seen in colorectal cancer (34). In addition, preliminary data from a German study suggested that TP53 R72P and MDM2 SNP309 may modulate the age at onset of breast cancer (35). We therefore investigated the combined effects of TP53 R72P and MDM2 SNP309 on breast cancer risk and the age at onset in breast cancer patients in a large pooled series of cases and controls from the BCAC. We also examined specifically the association of these polymorphisms with bilateral breast cancer and estrogen receptor–positive breast cancer.

	Materials and Methods

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Subjects. Breast cancer cases from five European studies within the BCAC, together with healthy controls from the same studies, were included in this analysis (Table 1 ). Three of the studies [Hannover Breast Cancer Study (HaBCS), Amsterdam Breast Cancer Study (ABCS), and British Breast Cancer (BBC)] specifically ascertained cases based on bilaterality. All breast cancers were invasive, except 13 cases in HaBCS and 23 cases in ABCS. All contributing groups included data on family history of breast cancer cases (data missing for 11% of the cases); some additional data on tumor grade were included from HaBCS, ABCS, and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH), and partial data on estrogen receptor status (negative or positive) were included from Helsinki Breast Cancer Study (HeBCS), HaBCS, ABCS, and SEARCH. All studies were approved by the appropriate (Medical) Ethical Research Committees.

Statistical methods. Deviations from the genotype frequencies in the controls from those expected under Hardy-Weinberg equilibrium were evaluated by a ² test (1 degree of freedom) for each study group separately. Breast cancer risks for each SNP were estimated as odds ratios (OR) for the rare homozygote, the heterozygote, and per-allele (each copy of rare allele) with the common homozygote as the referent category. Combined OR estimates across all studies were obtained using logistic regression by including study as a categorical covariate. Differences in mean and median among groups of common allele homozygotes, heterozygotes, and rare allele homozygotes were tested by ANOVA and Kruskal-Wallis tests, respectively. All statistical tests were two sided. All analyses were done using Statistical Package for the Social Sciences 12.01 (SPSS, Inc.).

	Results

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In total, 5,836 breast cancer cases (4,827 unilateral, 1,009 bilateral) and 4,673 controls were genotyped for MDM2 SNP309 and 8,345 cases (7,579 unilaterals, 766 bilaterals) and 6,849 controls were genotyped for TP53 R72P (Table 2 ). There was no evidence for deviation from the Hardy-Weinberg equilibrium for any of the individual control series, except for SNP309 in the SEARCH study (P = 0.004 for overall genotype distribution) where there was a shortage of heterozygotes (959 observed, 1,021 expected).

Table 3 summarizes the ORs for combined genotypes at TP53 R72P and MDM2 SNP309. In the pooled series, 4.5% of cases and controls were carriers of variant alleles of both SNPs [i.e., TP53 R72P CC (Pro/Pro) and MDM2 SNP309 GG or TG]. There was no evidence of a difference in the frequency of these combined genotypes between cases and controls. The median and mean ages at onset of the first breast cancer did not differ significantly between the different genotypes in MDM2 (median ages, 49, 49, and 50 years for genotypes TT, TG, and GG, respectively) or TP53 (median ages, 49, 50, and 50 years for GG, GC, and CC). Evidence for a slightly younger median age at onset for the combined MDM2 TG/GG TP53 CC genotype carriers was initially found in the HaBCS study (4 years younger; Table 3; ref. 35). However, in the pooled data set, after excluding the hypothesis-generating study, this effect was no longer apparent (Table 3; Fig. 1 ). In addition, there was no evidence for an association of breast cancer with the same combination of both SNPs (MDM2 TG/GG TP53 CC): OR, 1.00 (95% CI, 0.81–1.23; Table 3); this OR was similar for unilateral (1.01; 95% CI, 0.81–1.27) and bilateral breast cancer (0.95; 95% CI, 0.62–1.45). There was no indication for heterogeneity in the OR among contributing groups (P = 0.84).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Age at onset of the first breast cancer in combined variant alleles of MDM2 SNP309 (TT or TG/GG) and TP53 R72P [GG/GC (Arg/Arg Arg/Pro) or CC (Pro/Pro)] in HaBCS (German breast cancer series) and in the pooled breast cancer series (excluding HaBCS).

	Discussion

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We found no increased risk of breast cancer (unilateral or bilateral) or of earlier age at onset in the general population for carriers of the MDM2 SNP309 variant allele. We had already shown that if there was any association of TP53 R72P with breast cancer, it must be very weak (the upper 95% CI for rare homozygotes was 1.15 and for heterozygotes was 1.04; ref. 3). We have now shown that the same is true for MDM2 SNP309. This finding, in a very large study, confirms some earlier publications (18–23).

If anything, we found some evidence of a protective effect of the GG genotype of MDM2 (GG versus TG/TT: OR, 0.88; 95% CI, 0.79–0.99; P = 0.02; see Table 3); however, this would no longer be significant after adjusting for multiple testing. In addition, this protective effect seemed to be most apparent in the TP53 CC genotype (Table 3), which might suggest an interaction. However, this interaction was not found to be significant in a model including an interaction term for both SNPs (data not shown). Such an effect would probably only be expected if Mdm2 preferentially ubiquitinated the p53 Pro variant protein for degradation; as far as we know, this has not been reported. In addition, both the effect of the MDM2 GG genotype and the results in Table 3 were no longer significant after exclusion of the SEARCH study.

The general lack of evidence for effects of individual SNPs in association studies probably reflects that in fact only a small proportion of SNPs are associated with disease but also that most studies are underpowered to detect small effects (3, 9). However, it may also be that gene-gene and gene-environment interactions are of more importance than main effects (2). A plausible pair of candidates for a gene-gene interaction is TP53 and MDM2 based on their functions, known functional interaction, data in Li-Fraumeni patients (13), and preliminary data in German breast cancer patients (35). We investigated the interaction between these two SNPs in a large series of breast cancer patients, but we found that individuals with the presumed risk phenotype (i.e., CC in TP53 and GG or TG in MDM2) do not have a detectably increased risk of breast cancer. Although we pooled large numbers of cases and controls, it should be noted that we still had limited power to detect small interaction effects (80% power to detect interactions with an OR of >1.8, assuming an OR of 1.1 for both SNP309 and R72P; refs. 36, 37). It may also be that any or both of these SNPs (SNP309 and R72P) will have an effect in breast cancer only in interaction with other SNPs. After an initial stratification by genotype of the German hospital-based breast cancer series, we found evidence for an earlier age at onset but only for carriers of the putative risk MDM2 GT/TT and TP53 CC genotype (35). However, this finding could not be confirmed when this analysis was extended to the combined data set. Hence, the earlier age of onset in the German group is likely due to chance, although it might reflect differences in genetic background or environmental factors of that specific population.

The mean age of the German patients was higher than that in the pooled data set (Fig. 1). However, stratified analyses for age did not reveal earlier age at onset for any genotype specifically in the older age groups, neither within the German data set nor in the pooled data (data not shown). Although we found evidence for heterogeneity among contributing groups for MDM2 SNP309, which was attributable to the series from Finland, we did not consider this a reason for exclusion of these data. The ORs for SNP309 of Finland were in the range of the other groups and the higher proportion of MDM2 SNP309 G allele carriers may be due to the specific genetic background of the Finnish population, as the frequency distribution was close to that in another Finnish study (38).

We did not detect a difference for breast cancer risk or age at onset between cases from families with breast cancer or cases with no known other breast cancer cases in their family. The latter result is in line with the findings in non-BRCA1/2 families from another German study (20) but seems to contrast with one recently published study reporting a significantly increased proportion of MDM2 GG genotype in familial early cancer onset (diagnosed <51 years) compared with those with a late cancer onset (>51 years), 16% (of 271) versus 4% (of 72; ref. 39). Although it remains possible that the SNP309 only acts in synergy with a particular genetic background, in two additional series of familial breast cancer cases of the Netherlands Cancer Institute (Netherlands), namely, one randomly selected case per BRCA1 family (n = 95) and one randomly selected case ages <50 years per non-BRCA1/2 family (n = 244), SNP309 was not associated with earlier age at onset of breast cancer.¹⁰

In summary, in this large collaborative study, we did not find an indication for either an increase in risk or an earlier age at onset of breast cancer in carriers of either MDM2 SNP309 or TP53 R72P alone or in combination. This suggests that any effect of these two variants would be very small and, if present, confined to subgroups that were not separately assessed in our present study.

	Acknowledgments

 
Grant support: Academy of Finland (110663), Helsinki University Central Hospital Research Fund, Sigrid Juselius Fund, and Finnish Cancer Society (Finnish study); Cancer Research UK (SEARCH study); Dutch Cancer Society (NKI 2001-2423) and Cancer Genomics Center, Dutch Genomics Initiative (Dutch studies); and Cancer Research UK and Breakthrough Breast Cancer (BBC study and Mammography Oestrogens and Growth factors study). D.F. Easton is a Principal Research Fellow. P.D.P. Pharoah is a Senior Clinical Research Fellow of Cancer Research UK.

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.

We thank our Dutch colleagues at the Netherlands Cancer Institute (Roelof Pruntel, Siegina Klaver, Arnout van der Plas, Ben Nota, Flora van Leeuwen, and Hans Peterse) and Leiden University Medical Center (Vincent Smit, Cees Cornelisse, Nel Kuipers, and Rob Keizer) for their contributions; our German colleagues (Michael Bremer, Johann H. Karstens, Olaf Dammann, Peter Hillemanns, Alexander Scharf, and Christof Sohn) for their support of the study at Hannover Medical School; and Drs. Hannaleena Eerola and Kirsimari Aaltonen and R.N. Nina Puolakka (Helsinki University Central Hospital) for their help in patient contacts.

	Footnotes

 
Note: M.K. Schmidt and S. Reincke contributed equally to this work.

¹⁰ F.B.L. Hogervorst, unpublished data.

Received 2/26/07. Revised 6/ 7/07. Accepted 7/23/07.

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