Elsevier

The Lancet

Volume 366, Issue 9496, 29 October–4 November 2005, Pages 1554-1557
The Lancet

Articles
Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study

https://doi.org/10.1016/S0140-6736(05)67627-1Get rights and content

Summary

Background

The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele.

Methods

A population-based series of 469 bilateral breast cancer cases ascertained through English cancer registries were genotyped for CHEK2*1100delC. Standardised incidence ratios (SIRs) and cumulative risks were calculated for breast cancer, prostate cancer, and all other cancers in the first-degree relatives of carriers and non-carriers.

Findings

The relatives of bilateral cases who were wild-type for CHEK2 had three times the population risk of female breast cancer (145 cases: SIR 3·48 (95% CI 2·96–4·09), twice the risk of prostate cancer (34 cases: SIR 2·41, 1·67–3·36) and a large excess of male breast cancer (five cases: SIR 15·06, 4·92–35·36). Relatives of those who were carriers of CHEK2*1100delC had a substantially higher risk of breast cancer (eight cases: SIR 12·11, 5·23–23·88) and possibly prostate cancer (two cases: SIR 9·87, 1·20–35·67).

Interpretation

These data suggest a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. In women with a family history of bilateral disease, CHEK2*1100delC confers a high lifetime risk and might be useful for predictive testing. Bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast-cancer genes.

Introduction

Many breast cancers arise in a genetically susceptible minority of women,1 most of whom are not carriers of mutant BRCA1 or BRCA2.2 The excess familial breast cancer risk unaccounted for by BRCA1 and BRCA2 can be explained by a polygenic model in which many genes that confer low risks individually act in combination to cause a wide spectrum of risk in the population. One such model predicts that 50% of all breast cancer cases occur in the 12% of the population who are at greatest genetic risk, and that the risk varies between the extremes of the distribution by as much as 40 times.3 CHEK2*1100delC, which has a frequency of between 0·5% and 1·3% in white northern European populations, is a plausible candidate as a low-penetrance breast-cancer polygene. The breast cancer risk among carriers was double that in the population in a series of 10 860 unselected cases of breast cancer, and the allele probably confers a similar risk for prostate cancer in men.4, 5, 6, 7 Our aim was to determine the risk of breast cancer in relatives of women with bilateral breast cancer who carry the CHEK2*1100delC allele.

Section snippets

Population

A population-based series of 469 bilateral breast-cancer cases were ascertained through the English cancer registries. Women were eligible if they were white, they had had two sequential or simultaneous primary breast cancer registrations confirmed by interview as separate cancers, and their first cancer was diagnosed before age 65 years in 1971 or later. Date of birth, date of death, age at cancer diagnosis, and type of cancer were recorded for each first-degree relative from the index case by

Results

Almost a third (139 of 469, 29·6%) of bilateral breast cancer cases had at least one relative with breast cancer and 7·0% (33 of 469) had a relative with prostate cancer. The table shows SIRs for breast, prostate, and all other cancers in first-degree relatives. There were 153 female breast cancers (SIR 3·61) and 36 prostate cancers (SIR 2·51) in relatives. Male first-degree relatives of bilateral breast cancer cases also had a high rate of breast cancer. Of the 469 bilateral cases, seven

Discussion

The combined published data for the prevalence of CHEK2*1100delC in unselected breast cancers and population controls give an overall odds ratio of 2·34.4 The prevalence of CHEK2*1100delC in controls varies between 0·5% in England (21 of 4037, 95% CI 0·3–0·8), 1·0% in the Netherlands (nine of 909, 0·5–1·9), and 1·3% in Finland (31 of 2332, 0·9–1·9).4 The prevalence of 1·5% (seven of 469) in these bilateral cases is consistent with the relative risk in unselected cases (2·34, 1·72–3·20) and the

References (14)

  • X Dong et al.

    Mutations in CHEK2 associated with prostate cancer risk

    Am J Hum Genet

    (2003)
  • J Peto et al.

    High constant incidence in twins and other relatives of women with breast cancer

    Nat Genet

    (2000)
  • J Peto et al.

    Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer

    J Natl Cancer Inst

    (1999)
  • PD Pharoah et al.

    Polygenic susceptibility to breast cancer and implications for prevention

    Nat Genet

    (2002)
  • CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies

    Am J Hum Genet

    (2004)
  • EH Seppala et al.

    CHEK2 variants associate with hereditary prostate cancer

    Br J Cancer

    (2003)
  • C Cybulski et al.

    A novel founder CHEK2 mutation is associated with increased prostate cancer risk

    Cancer Res

    (2004)
There are more references available in the full text version of this article.

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    The PRS OR was also slightly attenuated after the adjustment. However, CHEK2*1100delC, PRS, and family history remained significant risk factors in the combined model (Table 2), suggesting that the common variants together explain part of the excess familial risk as previously suggested,16 but that the PRS also has predictive value in breast cancer families segregating CHEK2*1100delC. Recently, a large study estimating the risk associated with CHEK2*1100delC in relation to age, tumor subtype, and family history reported that the cumulative lifetime risk for 1100delC carriers was approximately 22%.13

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    Johnson et al. reported a cumulative breast cancer risk of 59% (95% CI: 34–85) in first degree relatives of CHEK2∗1100delC positive bilaterally affected breast cancer patients. Their results are well in line with our results.18 In our opinion, the difference in breast cancer risk between the non-BRCA1/2 familial groups in our study warrants CHEK2∗1100delC testing in a familial setting and adjusting breast surveillance accordingly.

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