RT Journal Article
SR Electronic
T1 Penetrance estimates for <em>BRCA1</em>, <em>BRCA2</em> (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2017-105223
DO 10.1136/jmedgenet-2017-105223
A1 D Gareth Evans
A1 Emma Woodward
A1 Elaine F Harkness
A1 Anthony Howell
A1 Inga Plaskocinska
A1 Eamonn R Maher
A1 Marc D Tischkowitz
A1 Fiona Lalloo
YR 2018
UL http://jmg.bmj.com/content/early/2018/02/26/jmedgenet-2017-105223.abstract
AB Purpose The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive.Methods We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2.Results Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1.Conclusion We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.