title: Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect.
abstract: Genetic anticipation, the earlier onset of disease in successive generations, has been reported in hereditary breast and ovarian cancer syndrome (HBOC), but little is known about its underlying mechanisms. Ascertainment bias has been suggested as a reason in previous studies. Likewise, cohort effect, which may be caused by environmental factors, can be misinterpreted as genetic anticipation.
  
  
  
  The authors reviewed the pedigrees of 176 kindreds, segregating those with deleterious mutations in breast cancer genes 1 and 2 (BRCA1/BRCA2) who had at least 2 consecutive generations of the same cancer (breast or ovarian). By using mutation probabilities as analytical weights in weighted random-effect models, generational differences in the age at onset of breast/ovarian cancer were calculated. The analyses were further controlled for ascertainment bias by excluding probands and adjusting for birth-cohort effect in the anticipation models.
  
  
  
  The mean age at the onset of breast cancer for the probands' generation was 41.9 years, which was 6.8 years and 9.8 years earlier than the parents' and grandparents' generations, respectively. The anticipation effect for breast cancer remained significant after excluding the probands. There was a birth-cohort effect: patients who were born in 1930s and 1940s had breast cancer 5.0 years and 7.6 years earlier than patients who were born before 1920. The difference in breast cancer age of onset across generations was no longer significant after adjusting for birth-cohort effect.
  
  
  
  The observed anticipation effect was driven mainly by a decrease in age of onset across birth cohorts, underscoring the need for risk-reducing interventions that target changing environmental/lifestyle factors in BRCA1/BRCA2 carriers. Cancer 2016;122:1913-20. © 2016 American Cancer Society.
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, Illinois.|Department of Radiology and Oncology, The State of Sao Paulo Cancer Institute, University of Sao Paulo Medical School, Sao Paulo, Brazil.|Clínica de Oncologia (CLION), Clínica de Assistência à Mulher (CAM) Group, Salvador, Bahia, Brazil.
authors.forename: Rodrigo Santa Cruz
authors.initials: RS
authors.lastname: Guindalini
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, Illinois.
authors.forename: Andrew
authors.initials: A
authors.lastname: Song
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, Illinois.
authors.forename: James D
authors.initials: JD
authors.lastname: Fackenthal
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, Illinois.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, Illinois.|Department of Public Health Sciences, The University of Chicago, Chicago, Illinois.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
mesh_terms: D000328:Adult; D000367:Age Factors; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree
keywords: ascertainment bias; breast cancer genes 1 and 2 (BRCA1/BRCA2); cohort effect; genetic anticipation; hereditary breast and ovarian cancer syndrome