TY - JOUR
T1 - Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - dos Santos Silva, Isabel
AU - Kilpivaara, Outi
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Nevanlinna, Heli
AU - Wasielewski, Marijke
AU - Meijers-Heijerboer, Hanne
AU - Broeks, Annegien
AU - Schmidt, Marjanka K.
AU - van't Veer, Laura J.
AU - Bremer, Michael
AU - Dörk, Thilo
AU - Chekmariova, Elena V.
AU - Sokolenko, Anna P.
AU - Imyanitov, Evgeny N.
AU - Hamann, Ute
AU - Rashid, Muhammad U.
AU - Brauch, Hiltrud
AU - Justenhoven, Christina
AU - Ashworth, Alan
AU - Peto, Julian
PY - 2009
Y1 - 2009
N2 - 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
AB - 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
U2 - https://doi.org/10.1158/1055-9965.EPI-08-0416
DO - https://doi.org/10.1158/1055-9965.EPI-08-0416
M3 - Article
C2 - 19124502
SN - 1055-9965
VL - 18
SP - 230
EP - 234
JO - Cancer epidemiology, biomarkers & prevention
JF - Cancer epidemiology, biomarkers & prevention
IS - 1
ER -