Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls.
If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2 1100delC should be approximately 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be approximately 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2 1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P(trend) = 0.0003) and Finland (P(trend) = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2 1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2 1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2 1100delC and other moderate penetrance alleles in women with a family history of breast cancer.
Fletcher
Olivia
O
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London United Kingdom.
Johnson
Nichola
N
Dos Santos Silva
Isabel
I
Kilpivaara
Outi
O
Aittomäki
Kristiina
K
Blomqvist
Carl
C
Nevanlinna
Heli
H
Wasielewski
Marijke
M
Meijers-Heijerboer
Hanne
H
Broeks
Annegien
A
Schmidt
Marjanka K
MK
Van't Veer
Laura J
LJ
Bremer
Michael
M
Dörk
Thilo
T
Chekmariova
Elena V
EV
Sokolenko
Anna P
AP
Imyanitov
Evgeny N
EN
Hamann
Ute
U
Rashid
Muhammad U
MU
Brauch
Hiltrud
H
Justenhoven
Christina
C
Ashworth
Alan
A
Peto
Julian
J
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D016009:Chi-Square Distribution; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018570:Risk Assessment
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases