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

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