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Change in the penetrance of founder BRCA1/2 mutations? A retrospective cohort study
  1. W D Foulkes1,
  2. J-S Brunet2,
  3. N Wong3,
  4. J Goffin4,
  5. P O Chappuis5
  1. 1Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
  2. 2Algorithme Pharma, Montreal, Quebec, Canada
  3. 3Cancer Prevention Research Unit, Sir M B Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
  4. 4Department of Oncology, McGill University, Montreal, Quebec, Canada and NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
  5. 5Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada and Divisions of Oncology and Medical Genetics, University Hospital, Geneva, Switzerland
  1. Correspondence to:
 Dr W D Foulkes, Division of Medical Genetics, McGill University Health Centre, Montreal General Hospital, Room L10-116, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada;
 william.foulkes{at}mcgill.ca

https://doi.org/10.1136/jmg.39.6.407

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    There has been much discussion regarding the penetrance of breast cancer in BRCA1/2 mutation carriers (hereafter “carriers”). Both genetic and epigenetic factors could be influencing the reported penetrance estimates. We wanted to establish whether the penetrance of BRCA1/2 mutations is changing over time. To limit the genetic variability, we studied a cohort of 292 Ashkenazi Jewish (AJ) women diagnosed with first primary invasive breast cancer between 1 January 1980 and 1 November 1995 at a single Montreal Hospital, without regard to family history. All women were diagnosed at less than 65 years of age. Pathology blocks were identified from all women and the three AJ founder mutations in BRCA1/2 (185delAG, 5382insC (BRCA1) and 6174delT (BRCA2)) were identified in archival samples using PCR based techniques described previously.1 We identified 41 (14%, 95% CI 10.2-18.6) BRCA1/2 carriers (31 in BRCA1 and 10 in BRCA2). The difference in mutation frequency between BRCA1 and BRCA2 carriers (10.6% v 3.4%) is statistically significant (Z=3.40, p=0.0007). Given that the population allele frequencies of AJ founder mutations in BRCA1 and BRCA2 are approximately equal (∼1%), this would suggest that BRCA1 has a higher penetrance than BRCA2 by age 65. This observation supports previous data from Canada.2 We then divided the data into quartiles by year of diagnosis and determined whether the proportion of mutation carriers was changing over time. The number of founder BRCA1/2 mutations per quartile of year of diagnosis increased from eight (11.0%) to 15 (20.5%) over the 15 year period of the study, and the χ2 p value for the trend in mean scores was 0.047 (table 1). This suggests that the penetrance of BRCA1/2 mutations to the age of 65 years is increasing. This is important, as previous studies of …

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