title: Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers.
abstract: BACKGROUND
  Polygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences.
  
  
  METHODS
  A 77 single-nucleotide polymorphism polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term.
  
  
  RESULTS
  PRS weighted by breast cancer overall estimates was found to be differentially associated with 1865 screen-detected and 782 interval cancers in the LIBRO-1 study {age-adjusted odds ratio (OR)perSD [95% confidence interval (CI)] 0.91 [0.83-0.99], P = 0.023}. The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates [ORperSD = 0.90 (0.82-0.98), P = 0.011]. This result was corroborated by two independent studies [combined ORperSD = 0.87 (0.76-1.00), P = 0.058] with no evidence of heterogeneity. When enriched for 'true' interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced [ORperSD = 0.74 (0.62-0.89), P = 0.001], with a significant interaction effect between PRS and mammographic density (Pinteraction = 0.017).
  
  
  CONCLUSIONS
  To our knowledge, this is the first report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm jingmei.li@ki.se.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: J
authors.initials: J
authors.lastname: Holm
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Cancer Center Karolinska.
authors.forename: J
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: M
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: H
authors.initials: H
authors.lastname: Darabi
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm.
authors.forename: L S
authors.initials: LS
authors.lastname: Lindström
authors.affiliation: Department of Cancer Screening, Stockholm-Gotland Regional Cancer Centre, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Törnberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: P
authors.initials: P
authors.lastname: Hall
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: K
authors.initials: K
authors.lastname: Czene
mesh_terms: D000328:Adult; D000368:Aged; D000071060:Breast Density; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics*; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities; D008327:Mammography / Q000379:methods*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012042:Registries; D013548:Sweden / Q000453:epidemiology; D059467:Transcriptome / Q000235:genetics*
keywords: personalized medicine; polygenic risk score