title: Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls.
abstract: 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.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London United Kingdom.
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.forename: Isabel
authors.initials: I
authors.lastname: Dos Santos Silva
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Marijke
authors.initials: M
authors.lastname: Wasielewski
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijerboer
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van't Veer
authors.forename: Michael
authors.initials: M
authors.lastname: Bremer
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Elena V
authors.initials: EV
authors.lastname: Chekmariova
authors.forename: Anna P
authors.initials: AP
authors.lastname: Sokolenko
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Muhammad U
authors.initials: MU
authors.lastname: Rashid
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
mesh_terms: 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
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases