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Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers
Annals of Oncology 22 (Supplement 1): i11–i17, 2011 doi:10.1093/annonc/mdq660
symposium article Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers R. L. Milne1 & A. C. Antoniou2*
Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS.
introduction Breast cancer and ovarian cancer are complex diseases, with both genetic and environmental factors involved in their etiology. While various hormonal and lifestyle factors have been identified as playing an important role in these two pathologies, many of them common to both [1–10], having a family history of disease is one of the strongest risk factors. Women with a first-degree relative affected with breast cancer are at an estimated twofold increased risk of breast cancer, compared with those with no family history [11]. Similarly, having a first-degree relative affected with ovarian cancer is associated with a threefold increased risk of ovarian cancer [8]. Several high-risk breast and ovarian cancer susceptibility variants have been identified to date, the most important in the context of genetic counseling being BRCA1 and BRCA2. Female carriers of deleterious BRCA1 and BRCA2 mutations are predisposed to high lifetime risks of breast and ovarian cancer. They are also at increased risk of pancreatic and possibly other cancers, while male mutation carriers are at increased risk of pancreas, prostate and breast cancer, the latter particularly if the mutation is in BRCA2 [12, 13]. Initial estimates, based on studies of selected multiple-case families, indicated that by age 70, 80% of carriers of mutations in BRCA1 and BRCA2 would develop breast cancer, and 60% of
*Correspondence to: Antonis Antoniou, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Tel: +44-1223-740163; Fax: +44-1223-740159; E-mail: [email protected]
BRCA1 mutation carriers and 30% of BRCA2 mutation carriers would develop ovarian cancer [14, 15]. However, lower average penetrance estimates were obtained by a meta-analysis of studies that sampled index patients independently of their family history: cumulative breast cancer risk to age 70 of 65% for BRCA1 mutation carriers and 45% for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 39% and 11% for BRCA1 and BRCA2 mutation carriers, respectively [16, 17]. In addition, it has been reported that penetrance estimates vary between, and within, mutation carrier families, by age at onset of the index case and by the type of cancer in the index case [16, 18, 19]. These observations, as well as that of a possible increased risk of breast cancer for mutation-negative women from carrier families [20, 21] are consistent with the hypothesis that cancer risks in BRCA1 and BRCA2 mutation carriers are modified by other factors, at least some of them genetic. Further evidence for genetic modifiers of risk comes from studies of other phenotypes, such as mammographic density, which are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers [22], but themselves have a strong genetic component [23]. Finally, segregation analysis studies have quantified the extent of genetic variation in breast cancer risk for BRCA1 and BRCA2 mutation carriers [17, 18] and demonstrated that models that allow for other genes to have a modifying effect on the breast cancer risks conferred by BRCA1 and BRCA2 mutations fit significantly better to familial data than models without a modifying component [17, 24].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Spain; 2Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK
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1
symposium article This review focuses on common genetic polymorphisms that modify the risk of breast and ovarian cancer in female BRCA1 and BRCA2 mutation carriers, based on the current evidence, and on their implications for cancer risk prediction in these women. It also explores the value of studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers in identifying genetic variants associated with different disease subtypes in the general population.
Common genetic modifiers of breast cancer risk for carriers of mutations in BRCA1 and BRCA2 have been identified in essentially three ways: studies of single nucleotide polymorphisms (SNPs) in candidate genes, studies of SNPs found in genome-wide association studies (GWAS) to be associated with breast cancer risk in the general population and GWAS carried out in mutation carriers.
candidate gene studies Several common polymorphisms in candidate genes have been investigated as potential modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers. These studies have concentrated largely on genes thought to be functionally relevant to the disease or to interact functionally with BRCA1 and/or BRCA2. Many positive associations have been reported, but all have either failed to replicate [25–30] or require definitive replication in larger studies [31]. The only exceptions to this have been RAD51-135G/C and CASP8-D302H. The RAD51 polymorphism has been studied previously as a candidate risk modifier in mutation carriers based on the fact that the RAD51 protein interacts directly with both BRCA1 and BRCA2 [19, 32, 33]. An analysis by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) [34] found that BRCA2 mutation carriers who have two copies of the ‘C’ allele at this locus have a threefold increased breast cancer risk compared with carriers with two copies of the ‘G’ allele [35]. In a separate study, the CIMBA investigated the polymorphism in the apoptosis-related gene CASP8 because it was found to be associated with reduced breast cancer in the general population, following initial positive findings from candidate gene association studies [36]. Results indicate that the minor allele of CASP8-D302H confers a reduction in breast cancer risk for BRCA1 mutation carriers that is similar in magnitude [per-allele hazard ratio (HR) 0.85] [37] to the reduction in risk for the general population (per-allele HR 0.88; Tables 1 and 2). SNPs found by GWAS to be associated with breast cancer risk in the general population Until recently, attention has been focused on SNPs with clear statistical evidence of association (P < 1027) with breast cancer risk in the general population as potential modifiers of risk in BRCA1 and BRCA2 mutation carriers. To date, 18 such loci have been identified, all but one (CASP8-D302H) by GWAS [36, 38–46]. Results for these SNPs in the general population are summarized in Table 1. These variants are
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generally common [minor allele frequency (MAF) ‡0.13] and have relatively small associated per-allele odds ratio (OR, all <1.30). Many of these SNPs are more strongly associated with estrogen receptor (ER)-positive disease than ER-negative disease. This observation is likely related to the fact that all but one of the published studies have been based on predominantly sporadic breast cancer cases of white European ancestry, a large majority (70%–80%) of which have ERpositive disease. Such variants have been considered potential modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers. To investigate this, the CIMBA has studied such loci in its large collection of BRCA1 and BRCA2 mutation carriers. Results have been published for six of these polymorphisms and these are summarized in Table 2. Two SNPs have been found to be associated with the risk of breast cancer for BRCA1 mutation carriers, rs3803662 in the TOX3/TNRC9 region and rs13387042 in 2q35 [49, 50]. On the other hand, five of the six polymorphisms studied were associated with breast cancer risk for BRCA2 mutation carriers [49, 50] (Table 2). The strongest evidence of association was for a polymorphism in the FGFR2 gene (P = 2 · 1028), for which each copy of a minor allele was estimated to confer an HR of 1.32. Of the six polymorphisms studied, only 8q24-rs13281615 was not significantly associated with breast cancer risk for BRCA2 mutation carriers, but the HR estimate (1.06) was similar to the per-allele OR estimate in the general population (1.08) [39]. This analysis was based on 5400 BRCA2 mutation carriers and it may be that much larger samples are required to detect such effects reliably. These results indicate that the GWAS-identified susceptibility SNPs for the general population are differentially associated with risk for BRCA1 and BRCA2 mutation carriers. BRCA1 and BRCA2 mutations are associated with different breast tumor characteristics. While mutations in both genes are associated with the development of higher grade tumors [51], breast cancers in BRCA2 mutation carriers are otherwise broadly similar to those diagnosed in the general population, which are predominantly ER positive. In contrast, breast cancers in BRCA1 mutation carriers have a distinct morphology, more often have a ‘basal’ phenotype [52, 53] and are predominantly ER negative. Lakhani et al. [54] estimated that 90% of breast cancers in BRCA1 mutation carriers are ER negative, compared with 35% for BRCA2 mutation carrier cases. Figure 1 summarizes for GWAS-identified SNPs, the associations observed in BRCA1 and BRCA2 mutation carriers, and the associations with ER-positive and ER-negative breast cancer in the general population. The pattern of association of these SNPs for mutation carriers, by gene, is consistent with that for breast cancer defined by ER status in the general population. That is, SNPs associated with the risk of ERnegative disease tend to be associated with risk for carriers of mutations in BRCA1, whereas those associated with ER-positive disease in the general population, which constitute the majority of the susceptibility variants identified to date by GWAS, tend to be associated with risk for carriers of mutations in BRCA2. It has therefore been suggested that the differences in the associations of these SNPs with breast cancer risk for BRCA1 versus BRCA2 mutation carriers could be explained by the differential effects of the underlying causal
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common variants associated with breast cancer risk for mutation carriers
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Table 1. SNPs associated with breast cancer risk in the general population Locus-SNP
Gene(s)
Freq.
P(het)
OR (ER+)
OR (ER–)
References
0.88
0.2
0.90
0.93*
[36]
1.26 1.20 1.13 1.08 1.07 1.12 1.19 1.11 0.95 0.84 1.14 1.15 1.09 0.94 0.86 1.07 1.15
10213 0.02 0.1 0.001 0.3 0.2 0.0042 0.02 0.0008 0.2 0.001 0.02** 0.2 0.9 0.2 0.9 0.2
1.31 1.23 1.12 1.13 1.07 1.14 1.27 1.12 0.94 0.83 1.16
1.08 1.14 1.07 1.03* 1.04* 1.10 1.05* 1.06 1.03* 0.97* 1.02*
1.09 0.94 0.83 1.08 1.17
1.00* 0.94* 0.91* 1.08* 1.07*
[39, 47] [39, 47] [39, 47] [39, 47] [39, 47] [40] [42] [38] [38] [43] [43] [44] [46] [46] [46] [46] [46]
0.99 1.01
3 · 1025 2 · 1026
0.91 1.07
1.21 0.83
[48] [48]
Freq., risk allele frequency (white Europeans); GWAS, genome-wide association studies; OR, per-risk-allele odds ratio; P(het), P-value for equality of ORs by estrogen receptor status; ER+, estrogen receptor-positive disease; ER–, estrogen receptor-negative disease; SNP, single nucleotide polymorphism. * No evidence of association observed for ER-negative disease (all P-values > 0.05) ** Evidence of a stronger association for ER-negative disease for Chinese women, although associations were highly statistically significant for both types of disease (both P-values < 1029). This was not assessed in women with white European ancestry.
Table 2. SNPs associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
Gene/region
SNP
BRCA1 No.carriers
HR(95% CI)a
SNPs identified through candidate gene studies RAD51 rs1801320 5778 1.59 (0.96–2.63)d CASP8 D302H 4844 0.85 (0.76–0.97) SNPs identified by GWAS to be associated with risk in the general FGFR2 rs2981522 6028 1.02 (0.95–1.09) TOX3/TNRC9 rs3803662 6294 1.11 (1.03–1.19) MAP3K1 rs889312 6741 0.99 (0.93–1.06) LSP1 rs3817198 8984 1.05 (0.99–1.11) 2q35 rs13387042 9031 1.14 (1.04–1.25)e 8q24 rs13281615 9016 1.00 (0.94–1.05) SNPs identified through GWAS of BRCA1 mutation carriers C19orf62/ANKLE1 rs8170 8363 1.26 (1.17–1.35) C19orf62/ANKLE1 rs2363956 8359 0.84 (0.80–0.89)
Pb
% Variance explainedc
BRCA2 No. carriers
HR(95% CI)a
Pb
% Variance explainedc
Ref.
0.07 – 0.01 0.4 population 0.6 – 0.004 0.3 0.9 – 0.90 – 0.005 0.2 0.9 –
2748 2509
3.18 (1.39–7.27)d 1.06 (0.88–1.27)
0.0004 0.6
1.3 –
[35] [37]
3263 3255 3524 5434 5449 5433
1.32 1.15 1.12 1.16 1.18 1.06
2·1028 0.009 0.02 0.0003 0.008 0.2
2.2 0.5 0.3 0.6 0.3 –
[48] [48] [48] [47] [47] [47]
2·1029 6·1029
2448 2461
0.90 (0.77–1.05) 1.12 (0.99–1.27)
0.2 0.07
– –
[53] [53]
1.3 1.1
(1.20–1.45) (1.03–1.27) (1.02–1.24) (1.07–1.25) (1.04–1.33)e (0.98–1.14)
a
Per-allele hazard ratio (HR) unless specified otherwise. P-value for test of association. c Proportion of the polygenic modifying variance explained [49]. d HR for genotype CC versus GG. e HR under a dominant model. GWAS, genome-wide association studies; SNP, single polymorphism. b
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SNPs identified through candidate gene studies 10p14-rs1045485 CASP8 0.13 SNPs identified by GWAS 10q26-rs2981582 FGFR2 0.38 16q12-rs3803662 TOX3/TNRC9 0.25 5q11-rs889312 MAP3K1 0.28 8q24-rs13281615 intergenic 0.40 11p15-rs3717198 LSP1, LOC643714 0.30 2q35-rs13387042 intergenic 0.52 5p12-rs10941679 MRPS30 0.26 3p24-rs4973768 NEK10, SLC4A7 0.46 17q23-rs6504950 COX11 0.27 14q24-rs999737 RAD51L1 0.24 1p11-rs11249433 intergenic 0.40 6q25-rs2046210 ESR1 0.34 9p21-rs1011970 CDKN2A, CDKN2B 0.17 10p15-rs2380205 ANKRD16, FBXO18 0.43 10q21-rs10995190 ZNF365 0.15 10q22-rs704010 ZMIZ1 0.39 11q13-rs614367 intergenic 0.15 SNPs identified through GWAS carried out in mutation carriers 19p13-rs8170 C19orf62 0.19 19p13-rs2363956 C19orf62 0.50
OR (overall)
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variants on the development of ER-defined subtypes of disease [49, 50].
GWAS in BRCA1 and BRCA2 mutation carriers The evidence from the studies described above indicates that genetic variants that modify breast cancer risk for BRCA1 mutation carriers may differ from those for BRCA2 carriers or for non-carriers. This led investigators to search for genetic loci associated with breast cancer for BRCA1 and BRCA2 mutation carriers through separate GWAS in each of the two groups using the CIMBA collection. Initial results have so far been reported for the BRCA1 mutation carrier GWAS as part of a fast replication two-stage experiment [48]. Two SNPs at locus 19p13 were independently associated with breast cancer risk. Based on the combined analysis of stages 1 and 2, each copy of the minor allele of SNP rs8170 was associated with an estimated HR of 1.26 [95% confidence interval (CI) 1.17–1.35], whereas each copy of the ‘C’ allele at SNP rs2363956 was associated with reduced breast cancer risk (HR 0.84; 95% CI 0.80–0.89). Modelling the joint effects of all significant SNPs in the region revealed that the most parsimonious model was one that included the effects of both rs8170 and rs2363956 (2df P = 10213), indicating that the association signal could be driven by a variant that is correlated with both these polymorphisms. SNP imputation analysis in the 19p13 region, using data from the 1000 genomes project data as reference, revealed a series of correlated SNPs with smaller P values. Fine-mapping of the region based on direct genotyping is underway, as is as a largescale replication of findings from stage 1. A population-based case–control study of these polymorphisms revealed that neither was associated with the overall risk of breast cancer (Table 1). However, when cases were stratified by ER status, both SNPs were found to be associated with the risk of ER-
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negative disease (Table 1) and the magnitude and direction of the associations were similar to those observed for BRCA1 mutation carriers. Both SNPs were also associated with triplenegative [ER-, PR- and human epidermal growth factor receptor 2 (HER2)-negative] disease in the population-bases study, which is consistent with the observation that the majority of breast tumors in BRCA1 mutation carriers exhibit a triple-negative phenotype [48]. SNP rs8170 is located within the C19orf62 gene, which encodes mediator of Rap80 interactions and targeting 40 kDa (MERIT40), a protein that interacts with BRCA1 in a protein complex. Further research is required to characterize the function of this locus.
common variants associated with ovarian cancer risk for mutation carriers Although a number of small studies have evaluated candidate genes as ovarian cancer risk modifiers [28], to date, no genetic modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers have been definitively identified. Studies of ovarian cancer risk modifiers are challenging because of the smaller number of mutation carriers diagnosed with ovarian cancer compared with breast cancer and therefore small studies tend to be underpowered to detect modifying effects reliably. In fact, only one SNP has been observed to be associated with ovarian cancer risk in the general population at a high level of statistical significance (P < 1027) [55]. The minor allele of 9p22-rs3814113, with a frequency of 32%, was associated with protection from ovarian cancer (per-allele OR 0.82). This association was stronger for serous tumors (OR 0.77), which are the most common histological subtype of ovarian cancer. This SNP is therefore a potential modifier of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, both of which also
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Figure 1. Estimated hazard ratios (HRs) for breast cancer associated with eight single nucleotide polymorphisms (SNPs) in BRCA1 and BRCA2 mutation carriers (Table 2) and estimated per-allele odds ratios (ORs) for estrogen receptor (ER)-positive (ER+) and ER-negative (ER–) disease in the general population (Table 1). The patterns of association for BRCA1 mutation carriers are similar to those for ER-negative disease in the general population and the hazard ratio estimates for BRCA2 mutation carriers are broadly consistent with the OR estimates for ER-positive disease in the general population.
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tend to develop serous tumors [56], although this is yet to be evaluated. Further ovarian cancer GWAS and combined analysis studies are underway and are likely to yield additional common susceptibility SNPs. As for breast cancer, additional studies of less common disease subtypes may also prove to be fruitful in this regard. These could also provide good candidates as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers and future studies will aim to investigate these. Evaluation of SNPs as ovarian cancer risk modifiers as part of the GWAS in mutation carriers is also currently ongoing.
Individually, the common modifying polymorphisms are associated with modest relative risks of breast cancer (HR £ 1.32, Table 2). Evidence from published studies to date indicates that these combine multiplicatively, with no evidence of statistical interaction [49, 50]. The combined relative risks can therefore be much larger, depending on the number of risk alleles that a mutation carrier has, and this may have implications for their clinical utility in terms of breast cancer risk prediction. For example, based on the combined relative risk associated with the FGFR2 and TOX3/TNRC9 polymorphisms, the absolute risk of developing breast cancer by age 80 for BRCA2 mutation carriers varies from 54% for those with no risk alleles (representing 20% of BRCA2 mutation carriers) to 82% for those with two copies of risk alleles at both loci (representing 1% of BRCA2 mutation carriers) [50]. The power of SNP profiles to predict breast cancer risk in the general population is currently limited because the SNPs identified to date explain only a small proportion of the total genetic variation in risk [57–59]. Nevertheless, risk profiles based on currently established susceptibility variants may have a role in the delivery of effective screening programs, and predictive power is expected to improve as more susceptibility loci are identified [57, 60]. Figure 2A shows the predicted absolute risk of developing breast cancer in the general
population by risk category, as determined by risk profiling based on the allele frequencies and associated relative risk estimates for the 18 established susceptibility polymorphisms (Table 1), and assuming that these combine multiplicatively on the risk scale. The 5% of women in the general population at lowest risk are expected to have an absolute lifetime risk of £5.7%, compared with an absolute lifetime risk of ‡19% for the 5% at highest risk. While the estimated relative risks associated with the susceptibility SNPs identified to date for mutation carriers are of similar magnitude to those for the same SNPs in the general population, their combined relative risks translate to much larger differences in the absolute risk of developing breast cancer for mutation carriers, because of their already elevated average risk of the disease. This is demonstrated by comparison of Figure 2A with Figure 2B, the latter showing the predicted absolute risk for developing breast cancer for BRCA2 mutation carriers, using the same 18 SNP profile. Not all of these 18 SNPs have been investigated in BRCA2 mutation carriers, and so it should be noted that Figure 2B gives the maximum potential risk discrimination that could be achieved assuming that all currently known breast cancer susceptibility alleles are also associated with the same relative risks of breast cancer for BRCA2 mutation carriers. Results obtained so far from the evaluation in BRCA2 mutation carriers of GWAS hits from the general population indicate that this may well be the case [49, 50]. According to this model, the 5% of the BRCA2 mutation carriers at lowest risk are predicted to have a lifetime breast cancer risk of £47%, compared with a lifetime risk of ‡89% for the 5% at highest risk. Such differences in absolute risk could potentially be informative in the genetic counseling process. Based on only the six SNPs that have been investigated in mutation carriers (Table 2) a more restricted risk range is predicted [49, 50]. As discussed previously, fewer of these SNPs have been found to be associated with breast cancer risk for BRCA1 mutation carriers. However, as more associations are identified through the ongoing BRCA1 mutation carrier GWAS, a similar separation in risk by SNP profile can be expected for these women at already high risk of breast cancer. In addition, it
Figure 2. Predicted age-specific cumulative breast cancer risks for a female from the general population (A) and for a BRCA2 mutation carrier (B) by percentiles of the combined genotype distribution based on 18 single nucleotide polymorphisms (SNPs) known to be associated with breast cancer risk in the general population (SNP details are provided in Table 1). The figures show the risks for an average individual and the risks for individuals at the 5th and 95th percentiles of the combined SNP distribution, assuming the same relative risks apply to the general population and to BRCA2 mutation carriers. Calendar-period-specific incidences for England and Wales were assumed for the general population; the average BRCA2 incidences were obtained from Antoniou et al. [17]. Risks apply to individuals born after 1950.
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implications for cancer risk prediction for mutation carriers
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symposium article appears reasonable to expected that genetic variants identified through GWAS restricted to ER-negative or triple-negative breast cancer, or through GWAS carried out in populations in which ER-negative disease is more common (such as the Asian and black populations) [44] may also be relevant for risk prediction in BRCA1 mutation carriers.
conclusions
acknowledgements ACA is a Cancer Research UK Senior Cancer Research Fellow.
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disclosures The authors declare no conflict of interest.
references 1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347: 1713–1727. 2. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047–1059. 3. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002; 360: 187–195. 4. Hamajima N, Hirose K, Tajima K et al. Alcohol, tobacco and breast cancer– collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002; 87: 1234–1245. 5. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993; 15: 36–47. 6. van den Brandt PA, Spiegelman D, Yaun SS et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000; 152: 514–527. 7. CDC Consortium. The reduction in risk of ovarian cancer associated with oralcontraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 1987; 316: 650–655. 8. Elmasry K, Gayther SA. Ovarian cancer aetiology: facts and fiction. J Fam Plann Reprod Health Care 2006; 32: 82–86. 9. Gwinn ML, Lee NC, Rhodes PH et al. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol 1990; 43: 559–568. 10. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992; 136: 1184–1203. 11. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 2001; 358: 1389–1399. 12. Thompson D, Easton DF. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002; 94: 1358–1365. 13. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310–1316. 14. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995; 56: 265–271. 15. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62: 676–689. 16. Antoniou A, Pharoah PD, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72: 1117–1130. 17. Antoniou AC, Cunningham AP, Peto J et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer 2008; 98: 1457–1466. 18. Begg CB, Haile RW, Borg A et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA 2008; 299: 194–201.
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GWAS to discover breast cancer susceptibility variants in the general population and, to a lesser extent candidate gene studies, have led to the identification of several genetic loci that modify breast cancer risk for BRCA1 and BRCA2 mutation carriers. However, the currently established modifier loci explain only a small proportion of the genetic variation in breast cancer risk in these women (2.2% in BRCA1 and 5.2% in BRCA2 mutation carriers, Table 2), indicating that additional modifiers of risk remain to be identified. Because the effect sizes are expected to be relatively small, studies with large numbers of mutation carriers will be required to identify such variants reliably [61]. Given the rarity of mutations in BRCA1 and BRCA2, this will be possible only through continued recruitment of mutation carriers as well as collaboration through international initiatives like the CIMBA. Initial results from the published GWAS of BRCA1 mutation carriers demonstrate that additional genetic modifiers of risk can be identified by applying this approach specifically to mutation carriers, and the large-scale replication stages of GWAS in both groups of mutation carriers are therefore eagerly anticipated. Furthermore, they indicate that GWAS targeted at specific breast cancer subtypes may also identify additional breast cancer susceptibility variants. In particular GWAS of BRCA1 mutation carriers may identify alleles associated with ER-negative disease and/or relevant to the development of basal tumors. Differences in the associations of the modifying polymorphisms with breast cancer risk for BRCA1 and BRCA2 mutation carriers are likely to reflect differences in the biology of tumor development in these two groups of women at high risk of breast cancer. The identification of such polymorphisms could therefore lead to a better understanding of the etiology of tumors in mutation carriers and also to the development of effective and more specific therapies for breast cancer in mutation carriers. In contrast to the general population, the modest effect sizes associated with susceptibility polymorphisms for mutation carriers could translate into clinically relevant differences in the absolute risks of developing the disease, particularly when combined with those of other established risk factors in mutation carriers, such as mammographic density [22] and mutation position [12, 62]. This indicates that BRCA1 and BRCA2 mutation carriers may be two of the first groups of individuals for whom clinical applications could be developed using the common cancer susceptibility variants.
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40. Milne RL, Benitez J, Nevanlinna H et al. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J Natl Cancer Inst 2009; 101: 1012–1018. 41. Stacey SN, Manolescu A, Sulem P et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007; 39: 865–869. 42. Stacey SN, Manolescu A, Sulem P et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2008; 40: 703–706. 43. Thomas G, Jacobs KB, Kraft P et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 2009; 41: 579–584. 44. Zheng W, Long J, Gao YT et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 2009; 41: 324–328. 45. Hunter DJ, Kraft P, Jacobs KB et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007; 39: 870–874. 46. Turnbull C, Ahmed S, Morrison J et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 2010; 42: 504–507. 47. Garcia-Closas M, Hall P, Nevanlinna H et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 2008; 4: e1000054. 48. Antoniou AC, Wang X, Fredericksen ZS et al. A genome-wide association study identifies a 19p13 locus that modifies the risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 2010; 42: 885–892. 49. Antoniou AC, Sinilnikova OM, McGuffog L et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 2009; 18: 4442–4456. 50. Antoniou AC, Spurdle AB, Sinilnikova OM et al. Common breast cancerpredisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 2008; 82: 937–948. 51. Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 1997; 349: 1505–1510. 52. Lakhani SR, Jacquemier J, Sloane JP et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998; 90: 1138–1145. 53. Da Silva L, Lakhani SR. Pathology of hereditary breast cancer. Mod Pathol 2010; 23 (Suppl 2): S46–S51. 54. Lakhani SR, Van De Vijver MJ, Jacquemier J et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002; 20: 2310–2318. 55. Song H, Ramus SJ, Tyrer J et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet 2009; 41: 996–1000. 56. Lakhani SR, Manek S, Penault-Llorca F et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 2004; 10: 2473–2481. 57. Clayton DG. Prediction and interaction in complex disease genetics: experience in type 1 diabetes. PLoS Genet 2009; 5: e1000540. 58. Wacholder S, Hartge P, Prentice R et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med 2010; 362: 986–993. 59. Kraft P, Wacholder S, Cornelis MC et al. Beyond odds ratios–communicating disease risk based on genetic profiles. Nat Rev Genet 2009; 10: 264–269. 60. Pharoah PD, Antoniou AC, Easton DF, Ponder BA. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 2008; 358: 2796–2803. 61. Antoniou AC, Chenevix-Trench G. Common genetic variants and cancer risk in Mendelian cancer syndromes. Curr Opin Genet Dev 2010; 20: 299–307. 62. Thompson D, Easton D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001; 68: 410–419.
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19. Simchoni S, Friedman E, Kaufman B et al. Familial clustering of sitespecific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA 2006; 103: 3770–3774. 20. Smith A, Moran A, Boyd MC et al. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 2007; 44: 10–15. 21. Goldgar D, Venne V, Conner T, Buys S. BRCA phenocopies or ascertainment bias? J Med Genet 2007; 44: e86; author reply e88. 22. Mitchell G, Antoniou AC, Warren R et al. Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Res 2006; 66: 1866–1872. 23. Boyd NF, Dite GS, Stone J et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 2002; 347: 886–894. 24. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 2004; 91: 1580–1590. 25. Couch FJ, Sinilnikova O, Vierkant RA et al. AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev 2007; 16: 1416–1421. 26. Spurdle AB, Antoniou AC, Duffy DL et al. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 2005; 7: R176–183. 27. Spurdle AB, Antoniou AC, Kelemen L et al. The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2006; 15: 76–79. 28. Spurdle AB, Fahey P, Chen X et al. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2009; 122: 281–285. 29. Osorio A, Milne RL, Pita G et al. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/ BRCA2 (CIMBA). Br J Cancer 2009; 101: 2048–2054. 30. Jakubowska A, Rozkrut D, Antoniou A et al. The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2010; 121: 639–649. 31. Neuhausen SL, Brummel S, Ding YC et al. Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. Breast Cancer Res 2009; 11: R76. 32. Rebbeck TR, Wang Y, Kantoff PW et al. Modification of BRCA1- and BRCA2associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res 2001; 61: 5420–5424. 33. Kadouri L, Kote-Jarai Z, Hubert A et al. A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer 2004; 90: 2002–2005. 34. Chenevix-Trench G, Milne RL, Antoniou AC et al. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 2007; 9: 104. 35. Antoniou AC, Sinilnikova OM, Simard J et al. RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 2007; 81: 1186–1200. 36. Cox A, Dunning AM, Garcia-Closas M et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007; 39: 352–358. 37. Engel C, Versmold B, Wappenschmidt B et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2010; Oct 26 [Epub ahead of print]. 38. Ahmed S, Thomas G, Ghoussaini M et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 2009; 41: 585–590. 39. Easton DF, Pooley KA, Dunning AM et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007; 447: 1087–1093.
symposium article
symposium article Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers R. L. Milne1 & A. C. Antoniou2*
Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS.
introduction Breast cancer and ovarian cancer are complex diseases, with both genetic and environmental factors involved in their etiology. While various hormonal and lifestyle factors have been identified as playing an important role in these two pathologies, many of them common to both [1–10], having a family history of disease is one of the strongest risk factors. Women with a first-degree relative affected with breast cancer are at an estimated twofold increased risk of breast cancer, compared with those with no family history [11]. Similarly, having a first-degree relative affected with ovarian cancer is associated with a threefold increased risk of ovarian cancer [8]. Several high-risk breast and ovarian cancer susceptibility variants have been identified to date, the most important in the context of genetic counseling being BRCA1 and BRCA2. Female carriers of deleterious BRCA1 and BRCA2 mutations are predisposed to high lifetime risks of breast and ovarian cancer. They are also at increased risk of pancreatic and possibly other cancers, while male mutation carriers are at increased risk of pancreas, prostate and breast cancer, the latter particularly if the mutation is in BRCA2 [12, 13]. Initial estimates, based on studies of selected multiple-case families, indicated that by age 70, 80% of carriers of mutations in BRCA1 and BRCA2 would develop breast cancer, and 60% of
*Correspondence to: Antonis Antoniou, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Tel: +44-1223-740163; Fax: +44-1223-740159; E-mail: [email protected]
BRCA1 mutation carriers and 30% of BRCA2 mutation carriers would develop ovarian cancer [14, 15]. However, lower average penetrance estimates were obtained by a meta-analysis of studies that sampled index patients independently of their family history: cumulative breast cancer risk to age 70 of 65% for BRCA1 mutation carriers and 45% for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 39% and 11% for BRCA1 and BRCA2 mutation carriers, respectively [16, 17]. In addition, it has been reported that penetrance estimates vary between, and within, mutation carrier families, by age at onset of the index case and by the type of cancer in the index case [16, 18, 19]. These observations, as well as that of a possible increased risk of breast cancer for mutation-negative women from carrier families [20, 21] are consistent with the hypothesis that cancer risks in BRCA1 and BRCA2 mutation carriers are modified by other factors, at least some of them genetic. Further evidence for genetic modifiers of risk comes from studies of other phenotypes, such as mammographic density, which are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers [22], but themselves have a strong genetic component [23]. Finally, segregation analysis studies have quantified the extent of genetic variation in breast cancer risk for BRCA1 and BRCA2 mutation carriers [17, 18] and demonstrated that models that allow for other genes to have a modifying effect on the breast cancer risks conferred by BRCA1 and BRCA2 mutations fit significantly better to familial data than models without a modifying component [17, 24].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Spain; 2Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK
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1
symposium article This review focuses on common genetic polymorphisms that modify the risk of breast and ovarian cancer in female BRCA1 and BRCA2 mutation carriers, based on the current evidence, and on their implications for cancer risk prediction in these women. It also explores the value of studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers in identifying genetic variants associated with different disease subtypes in the general population.
Common genetic modifiers of breast cancer risk for carriers of mutations in BRCA1 and BRCA2 have been identified in essentially three ways: studies of single nucleotide polymorphisms (SNPs) in candidate genes, studies of SNPs found in genome-wide association studies (GWAS) to be associated with breast cancer risk in the general population and GWAS carried out in mutation carriers.
candidate gene studies Several common polymorphisms in candidate genes have been investigated as potential modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers. These studies have concentrated largely on genes thought to be functionally relevant to the disease or to interact functionally with BRCA1 and/or BRCA2. Many positive associations have been reported, but all have either failed to replicate [25–30] or require definitive replication in larger studies [31]. The only exceptions to this have been RAD51-135G/C and CASP8-D302H. The RAD51 polymorphism has been studied previously as a candidate risk modifier in mutation carriers based on the fact that the RAD51 protein interacts directly with both BRCA1 and BRCA2 [19, 32, 33]. An analysis by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) [34] found that BRCA2 mutation carriers who have two copies of the ‘C’ allele at this locus have a threefold increased breast cancer risk compared with carriers with two copies of the ‘G’ allele [35]. In a separate study, the CIMBA investigated the polymorphism in the apoptosis-related gene CASP8 because it was found to be associated with reduced breast cancer in the general population, following initial positive findings from candidate gene association studies [36]. Results indicate that the minor allele of CASP8-D302H confers a reduction in breast cancer risk for BRCA1 mutation carriers that is similar in magnitude [per-allele hazard ratio (HR) 0.85] [37] to the reduction in risk for the general population (per-allele HR 0.88; Tables 1 and 2). SNPs found by GWAS to be associated with breast cancer risk in the general population Until recently, attention has been focused on SNPs with clear statistical evidence of association (P < 1027) with breast cancer risk in the general population as potential modifiers of risk in BRCA1 and BRCA2 mutation carriers. To date, 18 such loci have been identified, all but one (CASP8-D302H) by GWAS [36, 38–46]. Results for these SNPs in the general population are summarized in Table 1. These variants are
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generally common [minor allele frequency (MAF) ‡0.13] and have relatively small associated per-allele odds ratio (OR, all <1.30). Many of these SNPs are more strongly associated with estrogen receptor (ER)-positive disease than ER-negative disease. This observation is likely related to the fact that all but one of the published studies have been based on predominantly sporadic breast cancer cases of white European ancestry, a large majority (70%–80%) of which have ERpositive disease. Such variants have been considered potential modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers. To investigate this, the CIMBA has studied such loci in its large collection of BRCA1 and BRCA2 mutation carriers. Results have been published for six of these polymorphisms and these are summarized in Table 2. Two SNPs have been found to be associated with the risk of breast cancer for BRCA1 mutation carriers, rs3803662 in the TOX3/TNRC9 region and rs13387042 in 2q35 [49, 50]. On the other hand, five of the six polymorphisms studied were associated with breast cancer risk for BRCA2 mutation carriers [49, 50] (Table 2). The strongest evidence of association was for a polymorphism in the FGFR2 gene (P = 2 · 1028), for which each copy of a minor allele was estimated to confer an HR of 1.32. Of the six polymorphisms studied, only 8q24-rs13281615 was not significantly associated with breast cancer risk for BRCA2 mutation carriers, but the HR estimate (1.06) was similar to the per-allele OR estimate in the general population (1.08) [39]. This analysis was based on 5400 BRCA2 mutation carriers and it may be that much larger samples are required to detect such effects reliably. These results indicate that the GWAS-identified susceptibility SNPs for the general population are differentially associated with risk for BRCA1 and BRCA2 mutation carriers. BRCA1 and BRCA2 mutations are associated with different breast tumor characteristics. While mutations in both genes are associated with the development of higher grade tumors [51], breast cancers in BRCA2 mutation carriers are otherwise broadly similar to those diagnosed in the general population, which are predominantly ER positive. In contrast, breast cancers in BRCA1 mutation carriers have a distinct morphology, more often have a ‘basal’ phenotype [52, 53] and are predominantly ER negative. Lakhani et al. [54] estimated that 90% of breast cancers in BRCA1 mutation carriers are ER negative, compared with 35% for BRCA2 mutation carrier cases. Figure 1 summarizes for GWAS-identified SNPs, the associations observed in BRCA1 and BRCA2 mutation carriers, and the associations with ER-positive and ER-negative breast cancer in the general population. The pattern of association of these SNPs for mutation carriers, by gene, is consistent with that for breast cancer defined by ER status in the general population. That is, SNPs associated with the risk of ERnegative disease tend to be associated with risk for carriers of mutations in BRCA1, whereas those associated with ER-positive disease in the general population, which constitute the majority of the susceptibility variants identified to date by GWAS, tend to be associated with risk for carriers of mutations in BRCA2. It has therefore been suggested that the differences in the associations of these SNPs with breast cancer risk for BRCA1 versus BRCA2 mutation carriers could be explained by the differential effects of the underlying causal
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common variants associated with breast cancer risk for mutation carriers
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Table 1. SNPs associated with breast cancer risk in the general population Locus-SNP
Gene(s)
Freq.
P(het)
OR (ER+)
OR (ER–)
References
0.88
0.2
0.90
0.93*
[36]
1.26 1.20 1.13 1.08 1.07 1.12 1.19 1.11 0.95 0.84 1.14 1.15 1.09 0.94 0.86 1.07 1.15
10213 0.02 0.1 0.001 0.3 0.2 0.0042 0.02 0.0008 0.2 0.001 0.02** 0.2 0.9 0.2 0.9 0.2
1.31 1.23 1.12 1.13 1.07 1.14 1.27 1.12 0.94 0.83 1.16
1.08 1.14 1.07 1.03* 1.04* 1.10 1.05* 1.06 1.03* 0.97* 1.02*
1.09 0.94 0.83 1.08 1.17
1.00* 0.94* 0.91* 1.08* 1.07*
[39, 47] [39, 47] [39, 47] [39, 47] [39, 47] [40] [42] [38] [38] [43] [43] [44] [46] [46] [46] [46] [46]
0.99 1.01
3 · 1025 2 · 1026
0.91 1.07
1.21 0.83
[48] [48]
Freq., risk allele frequency (white Europeans); GWAS, genome-wide association studies; OR, per-risk-allele odds ratio; P(het), P-value for equality of ORs by estrogen receptor status; ER+, estrogen receptor-positive disease; ER–, estrogen receptor-negative disease; SNP, single nucleotide polymorphism. * No evidence of association observed for ER-negative disease (all P-values > 0.05) ** Evidence of a stronger association for ER-negative disease for Chinese women, although associations were highly statistically significant for both types of disease (both P-values < 1029). This was not assessed in women with white European ancestry.
Table 2. SNPs associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
Gene/region
SNP
BRCA1 No.carriers
HR(95% CI)a
SNPs identified through candidate gene studies RAD51 rs1801320 5778 1.59 (0.96–2.63)d CASP8 D302H 4844 0.85 (0.76–0.97) SNPs identified by GWAS to be associated with risk in the general FGFR2 rs2981522 6028 1.02 (0.95–1.09) TOX3/TNRC9 rs3803662 6294 1.11 (1.03–1.19) MAP3K1 rs889312 6741 0.99 (0.93–1.06) LSP1 rs3817198 8984 1.05 (0.99–1.11) 2q35 rs13387042 9031 1.14 (1.04–1.25)e 8q24 rs13281615 9016 1.00 (0.94–1.05) SNPs identified through GWAS of BRCA1 mutation carriers C19orf62/ANKLE1 rs8170 8363 1.26 (1.17–1.35) C19orf62/ANKLE1 rs2363956 8359 0.84 (0.80–0.89)
Pb
% Variance explainedc
BRCA2 No. carriers
HR(95% CI)a
Pb
% Variance explainedc
Ref.
0.07 – 0.01 0.4 population 0.6 – 0.004 0.3 0.9 – 0.90 – 0.005 0.2 0.9 –
2748 2509
3.18 (1.39–7.27)d 1.06 (0.88–1.27)
0.0004 0.6
1.3 –
[35] [37]
3263 3255 3524 5434 5449 5433
1.32 1.15 1.12 1.16 1.18 1.06
2·1028 0.009 0.02 0.0003 0.008 0.2
2.2 0.5 0.3 0.6 0.3 –
[48] [48] [48] [47] [47] [47]
2·1029 6·1029
2448 2461
0.90 (0.77–1.05) 1.12 (0.99–1.27)
0.2 0.07
– –
[53] [53]
1.3 1.1
(1.20–1.45) (1.03–1.27) (1.02–1.24) (1.07–1.25) (1.04–1.33)e (0.98–1.14)
a
Per-allele hazard ratio (HR) unless specified otherwise. P-value for test of association. c Proportion of the polygenic modifying variance explained [49]. d HR for genotype CC versus GG. e HR under a dominant model. GWAS, genome-wide association studies; SNP, single polymorphism. b
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SNPs identified through candidate gene studies 10p14-rs1045485 CASP8 0.13 SNPs identified by GWAS 10q26-rs2981582 FGFR2 0.38 16q12-rs3803662 TOX3/TNRC9 0.25 5q11-rs889312 MAP3K1 0.28 8q24-rs13281615 intergenic 0.40 11p15-rs3717198 LSP1, LOC643714 0.30 2q35-rs13387042 intergenic 0.52 5p12-rs10941679 MRPS30 0.26 3p24-rs4973768 NEK10, SLC4A7 0.46 17q23-rs6504950 COX11 0.27 14q24-rs999737 RAD51L1 0.24 1p11-rs11249433 intergenic 0.40 6q25-rs2046210 ESR1 0.34 9p21-rs1011970 CDKN2A, CDKN2B 0.17 10p15-rs2380205 ANKRD16, FBXO18 0.43 10q21-rs10995190 ZNF365 0.15 10q22-rs704010 ZMIZ1 0.39 11q13-rs614367 intergenic 0.15 SNPs identified through GWAS carried out in mutation carriers 19p13-rs8170 C19orf62 0.19 19p13-rs2363956 C19orf62 0.50
OR (overall)
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variants on the development of ER-defined subtypes of disease [49, 50].
GWAS in BRCA1 and BRCA2 mutation carriers The evidence from the studies described above indicates that genetic variants that modify breast cancer risk for BRCA1 mutation carriers may differ from those for BRCA2 carriers or for non-carriers. This led investigators to search for genetic loci associated with breast cancer for BRCA1 and BRCA2 mutation carriers through separate GWAS in each of the two groups using the CIMBA collection. Initial results have so far been reported for the BRCA1 mutation carrier GWAS as part of a fast replication two-stage experiment [48]. Two SNPs at locus 19p13 were independently associated with breast cancer risk. Based on the combined analysis of stages 1 and 2, each copy of the minor allele of SNP rs8170 was associated with an estimated HR of 1.26 [95% confidence interval (CI) 1.17–1.35], whereas each copy of the ‘C’ allele at SNP rs2363956 was associated with reduced breast cancer risk (HR 0.84; 95% CI 0.80–0.89). Modelling the joint effects of all significant SNPs in the region revealed that the most parsimonious model was one that included the effects of both rs8170 and rs2363956 (2df P = 10213), indicating that the association signal could be driven by a variant that is correlated with both these polymorphisms. SNP imputation analysis in the 19p13 region, using data from the 1000 genomes project data as reference, revealed a series of correlated SNPs with smaller P values. Fine-mapping of the region based on direct genotyping is underway, as is as a largescale replication of findings from stage 1. A population-based case–control study of these polymorphisms revealed that neither was associated with the overall risk of breast cancer (Table 1). However, when cases were stratified by ER status, both SNPs were found to be associated with the risk of ER-
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negative disease (Table 1) and the magnitude and direction of the associations were similar to those observed for BRCA1 mutation carriers. Both SNPs were also associated with triplenegative [ER-, PR- and human epidermal growth factor receptor 2 (HER2)-negative] disease in the population-bases study, which is consistent with the observation that the majority of breast tumors in BRCA1 mutation carriers exhibit a triple-negative phenotype [48]. SNP rs8170 is located within the C19orf62 gene, which encodes mediator of Rap80 interactions and targeting 40 kDa (MERIT40), a protein that interacts with BRCA1 in a protein complex. Further research is required to characterize the function of this locus.
common variants associated with ovarian cancer risk for mutation carriers Although a number of small studies have evaluated candidate genes as ovarian cancer risk modifiers [28], to date, no genetic modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers have been definitively identified. Studies of ovarian cancer risk modifiers are challenging because of the smaller number of mutation carriers diagnosed with ovarian cancer compared with breast cancer and therefore small studies tend to be underpowered to detect modifying effects reliably. In fact, only one SNP has been observed to be associated with ovarian cancer risk in the general population at a high level of statistical significance (P < 1027) [55]. The minor allele of 9p22-rs3814113, with a frequency of 32%, was associated with protection from ovarian cancer (per-allele OR 0.82). This association was stronger for serous tumors (OR 0.77), which are the most common histological subtype of ovarian cancer. This SNP is therefore a potential modifier of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, both of which also
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Figure 1. Estimated hazard ratios (HRs) for breast cancer associated with eight single nucleotide polymorphisms (SNPs) in BRCA1 and BRCA2 mutation carriers (Table 2) and estimated per-allele odds ratios (ORs) for estrogen receptor (ER)-positive (ER+) and ER-negative (ER–) disease in the general population (Table 1). The patterns of association for BRCA1 mutation carriers are similar to those for ER-negative disease in the general population and the hazard ratio estimates for BRCA2 mutation carriers are broadly consistent with the OR estimates for ER-positive disease in the general population.
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tend to develop serous tumors [56], although this is yet to be evaluated. Further ovarian cancer GWAS and combined analysis studies are underway and are likely to yield additional common susceptibility SNPs. As for breast cancer, additional studies of less common disease subtypes may also prove to be fruitful in this regard. These could also provide good candidates as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers and future studies will aim to investigate these. Evaluation of SNPs as ovarian cancer risk modifiers as part of the GWAS in mutation carriers is also currently ongoing.
Individually, the common modifying polymorphisms are associated with modest relative risks of breast cancer (HR £ 1.32, Table 2). Evidence from published studies to date indicates that these combine multiplicatively, with no evidence of statistical interaction [49, 50]. The combined relative risks can therefore be much larger, depending on the number of risk alleles that a mutation carrier has, and this may have implications for their clinical utility in terms of breast cancer risk prediction. For example, based on the combined relative risk associated with the FGFR2 and TOX3/TNRC9 polymorphisms, the absolute risk of developing breast cancer by age 80 for BRCA2 mutation carriers varies from 54% for those with no risk alleles (representing 20% of BRCA2 mutation carriers) to 82% for those with two copies of risk alleles at both loci (representing 1% of BRCA2 mutation carriers) [50]. The power of SNP profiles to predict breast cancer risk in the general population is currently limited because the SNPs identified to date explain only a small proportion of the total genetic variation in risk [57–59]. Nevertheless, risk profiles based on currently established susceptibility variants may have a role in the delivery of effective screening programs, and predictive power is expected to improve as more susceptibility loci are identified [57, 60]. Figure 2A shows the predicted absolute risk of developing breast cancer in the general
population by risk category, as determined by risk profiling based on the allele frequencies and associated relative risk estimates for the 18 established susceptibility polymorphisms (Table 1), and assuming that these combine multiplicatively on the risk scale. The 5% of women in the general population at lowest risk are expected to have an absolute lifetime risk of £5.7%, compared with an absolute lifetime risk of ‡19% for the 5% at highest risk. While the estimated relative risks associated with the susceptibility SNPs identified to date for mutation carriers are of similar magnitude to those for the same SNPs in the general population, their combined relative risks translate to much larger differences in the absolute risk of developing breast cancer for mutation carriers, because of their already elevated average risk of the disease. This is demonstrated by comparison of Figure 2A with Figure 2B, the latter showing the predicted absolute risk for developing breast cancer for BRCA2 mutation carriers, using the same 18 SNP profile. Not all of these 18 SNPs have been investigated in BRCA2 mutation carriers, and so it should be noted that Figure 2B gives the maximum potential risk discrimination that could be achieved assuming that all currently known breast cancer susceptibility alleles are also associated with the same relative risks of breast cancer for BRCA2 mutation carriers. Results obtained so far from the evaluation in BRCA2 mutation carriers of GWAS hits from the general population indicate that this may well be the case [49, 50]. According to this model, the 5% of the BRCA2 mutation carriers at lowest risk are predicted to have a lifetime breast cancer risk of £47%, compared with a lifetime risk of ‡89% for the 5% at highest risk. Such differences in absolute risk could potentially be informative in the genetic counseling process. Based on only the six SNPs that have been investigated in mutation carriers (Table 2) a more restricted risk range is predicted [49, 50]. As discussed previously, fewer of these SNPs have been found to be associated with breast cancer risk for BRCA1 mutation carriers. However, as more associations are identified through the ongoing BRCA1 mutation carrier GWAS, a similar separation in risk by SNP profile can be expected for these women at already high risk of breast cancer. In addition, it
Figure 2. Predicted age-specific cumulative breast cancer risks for a female from the general population (A) and for a BRCA2 mutation carrier (B) by percentiles of the combined genotype distribution based on 18 single nucleotide polymorphisms (SNPs) known to be associated with breast cancer risk in the general population (SNP details are provided in Table 1). The figures show the risks for an average individual and the risks for individuals at the 5th and 95th percentiles of the combined SNP distribution, assuming the same relative risks apply to the general population and to BRCA2 mutation carriers. Calendar-period-specific incidences for England and Wales were assumed for the general population; the average BRCA2 incidences were obtained from Antoniou et al. [17]. Risks apply to individuals born after 1950.
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implications for cancer risk prediction for mutation carriers
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symposium article appears reasonable to expected that genetic variants identified through GWAS restricted to ER-negative or triple-negative breast cancer, or through GWAS carried out in populations in which ER-negative disease is more common (such as the Asian and black populations) [44] may also be relevant for risk prediction in BRCA1 mutation carriers.
conclusions
acknowledgements ACA is a Cancer Research UK Senior Cancer Research Fellow.
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disclosures The authors declare no conflict of interest.
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GWAS to discover breast cancer susceptibility variants in the general population and, to a lesser extent candidate gene studies, have led to the identification of several genetic loci that modify breast cancer risk for BRCA1 and BRCA2 mutation carriers. However, the currently established modifier loci explain only a small proportion of the genetic variation in breast cancer risk in these women (2.2% in BRCA1 and 5.2% in BRCA2 mutation carriers, Table 2), indicating that additional modifiers of risk remain to be identified. Because the effect sizes are expected to be relatively small, studies with large numbers of mutation carriers will be required to identify such variants reliably [61]. Given the rarity of mutations in BRCA1 and BRCA2, this will be possible only through continued recruitment of mutation carriers as well as collaboration through international initiatives like the CIMBA. Initial results from the published GWAS of BRCA1 mutation carriers demonstrate that additional genetic modifiers of risk can be identified by applying this approach specifically to mutation carriers, and the large-scale replication stages of GWAS in both groups of mutation carriers are therefore eagerly anticipated. Furthermore, they indicate that GWAS targeted at specific breast cancer subtypes may also identify additional breast cancer susceptibility variants. In particular GWAS of BRCA1 mutation carriers may identify alleles associated with ER-negative disease and/or relevant to the development of basal tumors. Differences in the associations of the modifying polymorphisms with breast cancer risk for BRCA1 and BRCA2 mutation carriers are likely to reflect differences in the biology of tumor development in these two groups of women at high risk of breast cancer. The identification of such polymorphisms could therefore lead to a better understanding of the etiology of tumors in mutation carriers and also to the development of effective and more specific therapies for breast cancer in mutation carriers. In contrast to the general population, the modest effect sizes associated with susceptibility polymorphisms for mutation carriers could translate into clinically relevant differences in the absolute risks of developing the disease, particularly when combined with those of other established risk factors in mutation carriers, such as mammographic density [22] and mutation position [12, 62]. This indicates that BRCA1 and BRCA2 mutation carriers may be two of the first groups of individuals for whom clinical applications could be developed using the common cancer susceptibility variants.
Annals of Oncology
Annals of Oncology
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