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


RESULTS
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).


CONCLUSIONS
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.
Johnson
Nichola
N
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Fletcher
Olivia
O
Naceur-Lombardelli
Cristina
C
dos Santos Silva
Isabel
I
Ashworth
Alan
A
Peto
Julian
J
D000328:Adult; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D064447:Checkpoint Kinase 2; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D015995:Prevalence; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000302:isolation & purification; D012042:Registries; D006113:United Kingdom / Q000453:epidemiology
D004273:DNA, Neoplasm; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases