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Phenocopies in families seen by cancer geneticists
  1. P Sasieni
  1. Correspondence to:
 Professor P Sasieni
 Cancer Research UK Centre for Epidemiology, Mathematics & Statistics, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK; peter.sasieni{at}cancer.org.uk

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Smith et al1 present data showing high rates of breast cancer in first-degree relatives (FDRs) of BRCA1 or BRCA2 mutation carriers who do not share their relative’s mutation. The authors conclude that in high-risk families, women who test negative for the familial mutation have an increased risk of breast cancer consistent with genetic modifiers and should be offered surveillance. Here, we show by simulation that the observed increased incidence in non-carriers is no greater than would be expected given the study design, even assuming that such individuals are only at population risk. It is the selection of families with multiple affected individuals for referral to the genetics clinics and the inclusion of cases ascertained before referral that causes this artefact.

The standardised incidence ratio (SIR) in FDRs who tested negative in Smith’s study was 5.0 (95% CI 2.9 to 7.8). After adjustment to take account of the fact that women with breast cancer were more likely to have genetic testing than were unaffected family members, the estimated ratio was 3.2 (95% CI 2.0 to 4.9). Looking only at cases diagnosed after mutation testing, the SIR was non-significantly …

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