title: Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families.
abstract: The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case-control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26-1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case-control dataset (1.49 [1.38-1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O.Box 700, 00029 HUS, Helsinki, Finland.
authors.forename: Taru A
authors.initials: TA
authors.lastname: Muranen
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology and Department of Public Health and Primary Care;Strangeways Research Laboratory, Worts Causeway, University of Cambridge, Cambridge, CBI 8RN, UK.
authors.forename: Nasim
authors.initials: N
authors.lastname: Mavaddat
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O.Box 700, 00029 HUS, Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O.Box 700, 00029 HUS, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O.Box 700, 00029 HUS, Helsinki, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Pelttari
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology and Department of Public Health and Primary Care;Strangeways Research Laboratory, Worts Causeway, University of Cambridge, Cambridge, CBI 8RN, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Meilahdentie 2, P.O. Box 160, 00029 HUS, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, P.O. Box 180, 00029 HUS, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology and Department of Public Health and Primary Care;Strangeways Research Laboratory, Worts Causeway, University of Cambridge, Cambridge, CBI 8RN, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O.Box 700, 00029 HUS, Helsinki, Finland. heli.nevanlinna@hus.fi.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D020412:Multifactorial Inheritance; D010375:Pedigree
keywords: Breast cancer; Common variants; Hereditary; PRS; Risk