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Clinical Investigations |
Cancer Research United Kingdom Genetic Epidemiology Group [E. L. G., D. F. E.], Cancer Research Human Cancer Genetics Group, Department of Oncology [A. M. D., B. K., C. S. H., B. A. J. P., P. P. D. P.], and Department of Public Heath and Primary Care [N. E. D.], University of Cambridge, Cambridge CB1 8RN, United Kingdom, and Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [E. L. G.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have carried out a large, population-based breast cancer study in East Anglia, United Kingdom (the ABC3 Study) to investigate common polymorphisms in candidate genes for low penetrance breast cancer susceptibility. Candidate genes have included those in pathways involved in DNA DSB repair, steroid hormone metabolism and signaling, and carcinogen metabolism. These genes may also be determinants of clinical outcome.
Variation in DNA DSB repair capabilities may affect survival because of altered response to radiation or chemotherapy. DSBs are frequently induced by carcinogens, such as ionizing radiation, and they are particularly difficult to repair compared with other types of DNA damage. Many genes involved in DSB repair pathways have been characterized, including TP53, ATM, and the familial breast cancer genes BRCA1 and BRCA2 (reviewed in Ref. 3 ). Inability to correctly repair DSBs can lead to tumorigenesis (3) . Common variants of DSB-involved genes have been implicated in epidemiological studies of breast cancer risk (4) ,4 and somatic alterations of TP53 in breast cancer tumors have been shown to affect survival (5) . Studies of BRCA1 and BRCA2 mutations and survival time after breast cancer have had conflicting results (6, 7, 8, 9, 10) .
Genetic variants in hormone metabolism pathways are also good candidates for breast cancer risk and survival. Several epidemiological studies suggest a role for hormone metabolism genes in breast cancer risk (reviewed in Ref. 11 ), and a few small studies suggest an association of polymorphisms in androgen metabolism genes with survival after breast cancer (12, 13, 14, 15) .
Variants in xenobiotic or carcinogen metabolism genes have been well studied in relation to breast cancer risk, and relative risks of up to 1.5 have been suggested for both Phase I and Phase II enzymes (reviewed in Ref. 11 ). Three analyses of survival associated with polymorphisms in Phase II enzymes have been reported (16, 17, 18) , although these studies were small. Sweeney et al. and Ambrosone et al. (17 , 18) observed protective effects of GSTP1, GSTM1, and GSTT1 null polymorphisms, whereas Lizard-Nacol et al. (16) found no difference in survival for women with a GSTM1 null genotype.
We have linked the genetic data from the ABC Study to outcome data from regional cancer registries to test the hypothesis that germ-line variants in these metabolic pathways affect survival after diagnosis of breast cancer. Genotyping data were available for polymorphisms in: ATM, BRCA1, BRCA2, CHK2, KU70, LIG4, NBS1, RAD51, RAD52, TP53, XRCC2, and XRCC3 from the DSB DNA repair pathway; AR, COMT, CYP17, CYP19, NQO1, and VDR from the hormone metabolism and signaling pathway; CYP1A1 and GSTP1 from the carcinogen metabolism pathway; and TGF-ß and CDH1, which are both somatically altered in breast cancer tumors. In addition, a subset of 1370 cases was screened for mutations in BRCA1 and BRCA2, and we compared survival in those patients who carry a protein truncating mutation with noncarriers.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2.2 million). Eligible cases are: (a) all cases of invasive breast cancer diagnosed at 
65 years of age since the beginning of the study on July 1, 1996 (incident cases); and (b) all cases diagnosed at 55 years of age since January 1, 1991 who were still alive at the beginning of the study (prevalent cases). Cancer registry boundary changes have meant that some prevalent cases diagnosed before 1995 were identified through the North Thames Cancer Registry. Cases diagnosed after January 1, 1991 who did not survive until July 1, 1996 are not included in the study, and so the data are left-truncated. Approximately 70% of eligible cases have enrolled in the study. The study is approved by the relevant Local Research Ethics Committees. There were 2473 participants enrolled in the ABC Study at the time of this analysis; all of the patients participating provided informed consent, submitted a blood sample, and completed a comprehensive questionnaire.
Genotyping.
Genotyping was performed in the course of ongoing analyses of candidate low penetrance breast cancer susceptibility genes. Cases were genotyped for the common SNPs and the VNTR polymorphisms shown in Table 2
. The number of cases genotyped varied for different polymorphisms because genotyping and case collection is ongoing, and fewer cases were available when the first polymorphisms were assayed >5 years ago [e.g., CYP19 (ttta)n and CYP17 c-34t]. Most SNPs were genotyped using a fluorescent 5' exonuclease assay (Taqman) and the ABI PRISM 7700 Sequence Detection System (PE Biosystems). In our laboratory, repeated genotyping of 14 different SNPs by this methods has been found to give >98% reproducibility.5
Allele sizing on an ABI373 sequencer (PE Biosystems) was used to genotype VNTRs. Additional details of SNP identification and genotyping procedures are available in the references shown in Table 2
or from the authors. BRCA1 and BRCA2 mutation analysis was carried out by heteroduplex analysis with sequencing confirmation as described previously (20)
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Statistical Methods.
Cox regression analysis (21)
allowing for left-truncated data were used to estimate genotype-specific HRs and 95% CIs in Stata version 6.0. The proportional hazards assumption was examined using log-log plots and tested formally by adding a time x genotype interaction term to the model. Time at risk began at date of blood sample receipt and ended at date of death from any cause, or, if death did not occur, September 30, 2000 (3 months before the start of this analysis). For each SNP, HRs were calculated with common allele homozygotes as the referent group (unless otherwise specified), and Ps presented indicate the significance of a test for heterogeneity among all three of the genotype groups (common allele homozygote, heterozygote, and rare allele homozygote).
Data on age at diagnosis, cancer stage, histological grade, and tumor type, was available from the registries for 1709 cases (70%). This enabled us to examine the significance of each polymorphism conditional on known prognostic factors. Factors were grouped as follows: age at diagnosis (< 45, 45–49, 50–53, and >53 years); tumor grade (well-differentiated, moderately differentiated, and poorly/undifferentiated); stage (Tumor-Node-Metastasis stages I-IV; Ref. 22
); and histological subtype (ductal, lobular, tubular, medullary, mucinous, metaplastic, and other). Initial analyses were not controlled for stage, grade, tumor type, or age at diagnosis, because any effect of genotype may act through these prognostic variables. If an unadjusted HR was significant at the 
= 0.05 level, likelihood ratio testing of the inclusion of covariates and interaction terms was performed to determine the best-fitting model. To avoid the proportional hazards assumption for other covariates, we then used "true" stratification for prognostic factors (as opposed to adjustment by inclusion of dummy covariates), so that baseline hazards could vary by strata (23)
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. More than 99% of the cases are white Anglo-Saxon. There were 1231 cases (51%) enrolled as incident cases, whereas 1199 (49%) were enrolled as prevalent cases. No difference in survival was observed between prevalent and incident cases in this sample (P = 0.54). Two hundred deaths occurred during a total of 6662 person-years at risk, and the overall 5-year survival rate was 86% (84–88%). This rate is slightly more than 5-year survival rate of 83% for all of the eligible cases, perhaps reflecting a "healthy study participant" effect.
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Protein-truncating Mutations in BRCA1 and BRCA2.
BRCA1 and BRCA2 mutation screening was performed on 1370 cases. Penetrance and prevalence estimates from this population have been reported previously (20)
. Ten cases were observed to have a mutation in BRCA1: 1619deltaaat, 2379delg, 2774delc, 2800delaa, 3596delaaag, 3874deltgtc, 3879del4, 4158delag, 4184deltcaa, and 4912 + 2delt. Unadjusted survival analysis showed that BRCA1 mutation carriers had poorer survival compared with noncarriers and untested cases [HR, 4.14 (1.32 – 13.0); P = 0.047] (Fig. 1)
. Restricting analyses to the 1370 women screened produced similar results. BRCA1 mutation carriers were significantly younger at diagnosis (P = 0.003) and had higher grade tumors (P = 0.02), but there was no significant association with stage or tumor type (P = 0.17 and P = 0.08, respectively). After adjustment for grade and tumor type, the effect of BRCA1 status was reduced and no longer significantly associated with prognosis [HRstratified, 1.99 (0.47–8.45)].
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Polymorphisms in DNA DSB Repair Genes.
Ligase IV is involved with nonhomologous end joining repair of DSBs. A silent t>c polymorphism in codon 501 (D501D) of the ligase IV gene (LIG4) was significantly associated with survival after breast cancer diagnosis (P = 0.002). Rare allele homozygotes (cc; n = 36) showed a 4-fold risk of death compared with common allele homozygotes (tt; n = 1,440) [HR, 4.01 (2.09–7.68)]. LIG4 heterozygotes (tc; n = 538) had a risk similar to that of the common allele homozygotes (tt) [HR, 1.01 (0.70–1.45)]. Additional analyses were performed by comparing rare allele homozygotes with the other two groups combined. Variables for age at diagnosis, grade, stage, tumor type, and prevalent/incident status were then included in the Cox regression analysis. After excluding factors not significant at the 5% level, the best fitting model included grade, stage, and tumor type. With adjustment for these variables, the rare allele homozygotes (cc; n = 26) remained at significantly increased risk of death compared with other genotypes (tt and tc; n = 1444) [HRstratified, 4.15 (1.85–9.30); P = 0.003]. There were no significant interactions between LIG4 genotype and grade, stage, or tumor type.
Like LIG4, KU70 is involved in the repair of DNA double-strand breaks through nonhomologous end joining. A silent g>t polymorphism at codon 593 did not affect breast cancer survival (P = 0.78). Six genes involved in homologous recombinational repair of DNA double-strand breaks were examined: ATM, BRCA1, BRCA2, RAD51, RAD52, and XRCC3. No polymorphism in these genes was associated with survival after breast cancer (Table 2)
. The gene for Nijmegen breakage syndrome (NBS1) is thought to be involved in DSB repair and cell cycle checkpoint functions. Four polymorphisms in NBS1 were examined; although rare homozygotes for all four of the polymorphisms appeared to have decreased risk of death compared with common homozygotes (HRs ranged from 0.58 to 0.79), no difference in risk was significant.
TP53 and CHK2 play roles in the cellular response to DSBs through the arrest of the cell cycle. We found a protective effect against death after breast cancer among cases that carried the proline allele of the TP53 R72P polymorphisms [heterozygote HR, 0.67 (0.48–0.94); rare allele homozygote HR, 0.77 (0.40–1.47)], although no significant heterogeneity existed among genotypes (P = 0.056). Considering heterozygotes and Pro-Pro homozygotes together, the estimated HR compared with Arg-Arg homozygotes was 0.68 (0.50–0.94; P = 0.018). Inclusion of known prognostic variables in the model reduced the apparent protective effect of this TP53 polymorphism [Pro carriers HR, 0.78 (0.52–1.15)]. The polymorphisms in CHK2 did not appear to affect survival after breast cancer.
Polymorphisms in Hormone Metabolism Genes.
There were 350 women genotyped at the intron 4 (ttta)n repeat in CYP19. There was a significant improvement in survival with increasing repeat length considered as a continuous covariate [HR, 0.85 (0.75–0.96); P = 0.01]. However, stratification by grade, stage, and tumor type reduced the dataset to 154 cases, and the effect was no longer significant [HR, 0.87 (0.70–1.08); P = 0.20)]. Data on 1527 women were available for the CYP19 c>t polymorphism, which had no effect on survival.
The CYP17 promoter t-34c had a marginally significant effect on breast cancer survival (P = 0.05). Heterozygotes had significantly increased hazard of death [HR, 1.81 (1.10–2.97)] compared with CYP17 common homozygotes, but this was no longer significant after adjustment for stage, grade, and tumor type [HR, 1.70 (0.86–3.37)]. An increased hazard in rare homozygotes was not significant [HR, 1.38 (0.70–2.75)]. Nonsignificant increased risks were also observed for the VDR gene (Table 2)
. None of the four SNPs in COMT was associated with survival nor were the total number of repeats at the AR exon 1 repeat polymorphisms [poly(Gln)n and poly(Gly)n] associated with time to death.
Polymorphisms in Other Genes.
Four genes involved in the metabolism of carcinogens and other xenobiotics were analyzed: ADH3, which catalyzes the oxidation and reduction of alcohols and aldehydes; CYP1A1, which is involved with Phase I detoxification of polycyclic aromatic compounds; GSTP1, which is involved with Phase II detoxification of carcinogens and their intermediates; and NQO1, which detoxifies quinones derived from oxidation of phenolic metabolites of benzene. In addition, TGF-ß and E-cadherin (CDH1) polymorphisms were assessed. No effect on survival by polymorphisms in any of these genes was observed (Table 2)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We observed a decreased survival in carriers of BRCA1 protein-truncating mutations that was attenuated by adjusting for tumor grade. This result is consistent with those of Foulkes et al. (6) , who studied 118 Ashkenazi Jewish breast cancer patients and found that 16 mutation carriers had poorer survival after adjustment for other prognostic factors, and Ansquer et al. (7) , who found that 15 mutation carriers among 123 women diagnosed under 36 years had tumors of higher grade and had poorer survival. Similarly, Eerola et al. (8) found that 32 patients in Finnish BRCA1 families had poorer survival (although not significantly) than patients in a sporadic control group. However, other studies have found no difference in survival (9) or improved survival (10) in BRCA1 mutation carriers. The latter two studies may have been biased by the preferential inclusion of carriers who are long-term survivors. In our study, such bias has been eliminated because women were unselected for family history or BRCA1/2 carrier status. We observed no effect of BRCA2 mutations on survival after breast cancer, consistent with studies published previously (8 , 24) .
The D501D polymorphism in LIG4 that was associated with prognosis does not alter the amino acid sequence of the protein and is therefore unlikely to have any functional effect. This suggests that the polymorphism may be in linkage disequilibrium with another, functional polymorphism. Identification of additional SNPs in LIG4 will enable assignment of haplotypes to cases and examination of ancestral haplotype effects on survival. However, the observed result should be interpreted with caution because of the few LIG4 cc homozygotes (n = 36). In addition, given the many polymorphisms examined, an adjustment needs to be made for multiple comparisons. We assessed 40 polymorphisms in 22 genes, so a conservative adjustment would allow for 40 individual comparisons. In this case, two associations would be expected to be significant at the 5% level by chance (against three observed), and the probability of an association as significant as LIG4 is only 0.08. However, because more than one polymorphism was tested in some genes, the results are not independent. If the adjustment is made for the 22 genes analyzed, the LIG4 result remains significant (P = 0.042). Data on type of treatment received by cases here was incomplete, so it remains unclear whether the LIG4 effect is because of an altered response to radiation or chemotherapy in particular. Clearly, it will be essential to attempt replication of this association in other datasets.
Analyses of an intronic CYP19 (ttta)n polymorphism suggested improved survival with longer repeat length. However, this analysis was based on only 350 women. In addition, a result of borderline significance was seen for CYP17 c-34t, which creates a fifth Sp-1 binding site in the promoter. This variant has not been shown to have a functional effect. Studies to identify functional changes in both CYP19 and CYP17 are in progress and, once identified, their analysis in a larger sample size will be indicated. The finding that TP53 P72 allele carriers have improved survival over noncarriers in unadjusted analyses is interesting because somatic mutations in this gene are known to be associated with an altered prognosis. Inclusion of known prognostic variables reduced the observed effect, suggesting that this TP53 polymorphism may predispose to less severe disease.
Even if confirmed, the genetic markers of prognosis identified by this study are unlikely to replace the conventional markers of prognosis. However, the results do support the notion that germ-line genetic variation will provide useful prognostic markers. Understanding the mechanism of action of these markers will provide insight into the biological determinants of response to treatment and prognosis in breast cancer, and opens up the possibility of a rational, targeted approach to cancer treatment based on a combination of genotype and tumor characteristics of a patient.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a program grant from the Cancer Research United Kingdom and a project grant from the National Health Service Research and Development. E. L. G. was supported by a Burroughs Wellcome Fund Research Travel Grant. B. A. J. P. is a Gibb Fellow, D. F. E. is a Principal Research Fellow, and P. D. P. P. is a Senior Clinical Research Fellow of Cancer Research United Kingdom. 
2 To whom requests for reprints should be addressed, at Department of Oncology, University of Cambridge, Strangeway’s Research Laboratories, Wort’s Causeway, Cambridge CB1 8RN. Phone: 44-1223-740166; Fax: 44-1223-411609; E-mail: paul.pharoah{at}srl.cam.ac.uk
3 The abbreviations used are: ABC, Anglian Breast Cancer; DSB, double strand break; SNP, single nucleotide polymorphism; VNTR, variable number of tandem repeat; HR, hazard ratio; CI, confidence interval.
4 B. Kuschel, A. Auranen, S. McBride, K. Novik, A. Antoniou, D. F. Easton, B. A. J. Ponder, P. D. P. Pharoah, and A. M. Dunning. Association between DNA double strand repair gene variants and low penetrance breast cancer susceptibility, manuscript in preparation.
Received 12/ 3/01. Accepted 3/22/02.
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REFERENCES |
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-reductase gene and breast cancer. Cancer Epidemiol. Biomark. Prev., 9: 387-393, 2000.-reductase gene in primary breast cancer. Br. J. Cancer, 84: 760-767, 2001.[Medline]
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