ArticlesInteraction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study
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.
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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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Towards precision prevention: Technologies for identifying healthy individuals with high risk of disease
2017, Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisGenetic modifiers of CHEK2∗1100delC-associated breast cancer risk
2017, Genetics in MedicineCitation Excerpt :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
Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model
2016, Genetics in MedicineCitation Excerpt :This assumes the effects of each variant and the residual polygene are multiplicative, which agrees with recent findings for PALB2.20 This model is also consistent with the higher RR for CHEK2 1100delC for BC based on familial cases,21,22 the higher RR for bilateral BC,23 and the increased risk in relatives of BC patients who are CHEK2 carriers.24 A higher RR for familial BC for ATM carriers has also been found, although data are more limited.25
Excess breast cancer risk in first degree relatives of CHEK2* 1100delC positive familial breast cancer cases
2013, European Journal of CancerCitation Excerpt :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.
Cancer of the Breast and Female Reproductive Tract
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsGene-panel sequencing and the prediction of breast-cancer risk
2015, New England Journal of MedicineCitation Excerpt :A broader question is that of how the risks associated with genetic variants should be combined with risk factors associated with lifestyle. Several studies indicate that the risks associated with common SNPs and other risk factors combine in a multiplicative rather than an additive fashion,72–74 and it would be reasonable to assume that rare variants combine with other risk factors in a similar manner. The evidence regarding the combined effects of genetic and lifestyle factors is both limited and conflicting for variants in BRCA1 and BRCA2,75 and no evidence is available for other genes.