Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

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Muranen , T A , Greco , D , Blomqvist , C , Aittomäki , K , Khan , S , Hogervorst , F , Verhoef , S , Pharoah , P D P , Dunning , A M , Shah , M , Luben , R , Bojesen , S E , Nordestgaard , B G , Schoemaker , M , Swerdlow , A , Garcia-Closas , M , Figueroa , J , Doerk , T , Bogdanova , N V , Hall , P , Li , J , Khusnutdinova , E , Bermisheva , M , Kristensen , V , Borresen-Dale , A-L , Peto , J , Silva , I D S , Couch , F J , Olson , J E , Hillemans , P , Park-Simon , T-W , Brauch , H , Hamann , U , Burwinkel , B , Marme , F , Meindl , A , Schmutzler , R K , Cox , A , Cross , S S , Sawyer , E J , Tomlinson , I , Lambrechts , D , Moisse , M , Lindblom , A , Margolin , S , Hollestelle , A , Martens , J W M , Fasching , P A , Beckmann , M W , Nevanlinna , H , NBCS Investigators , KConFab AOCS Investigators & Breast Canc Assoc Consortium 2017 , ' Genetic modifiers of CHEK2*1100delC-associated breast cancer risk ' , Genetics In medicine , vol. 19 , no. 5 , pp. 599-603 . https://doi.org/10.1038/gim.2016.147

Title: Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
Author: Muranen, Taru A.; Greco, Dario; Blomqvist, Carl; Aittomäki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Bojesen, Stig E.; Nordestgaard, Borge G.; Schoemaker, Minouk; Swerdlow, Anthony; Garcia-Closas, Montserrat; Figueroa, Jonine; Doerk, Thilo; Bogdanova, Natalia V.; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Peto, Julian; Silva, Isabel dos Santos; Couch, Fergus J.; Olson, Janet E.; Hillemans, Peter; Park-Simon, Tjoung-Won; Brauch, Hiltrud; Hamann, Ute; Burwinkel, Barbara; Marme, Frederik; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor J.; Tomlinson, Ian; Lambrechts, Diether; Moisse, Matthieu; Lindblom, Annika; Margolin, Sara; Hollestelle, Antoinette; Martens, John W. M.; Fasching, Peter A.; Beckmann, Matthias W.; Nevanlinna, Heli; NBCS Investigators; KConFab AOCS Investigators; Breast Canc Assoc Consortium
Contributor: University of Helsinki, Department of Obstetrics and Gynecology
University of Helsinki, Clinicum
University of Helsinki, Medicum
University of Helsinki, Department of Obstetrics and Gynecology
University of Helsinki, Department of Obstetrics and Gynecology
Date: 2017-05
Language: eng
Number of pages: 5
Belongs to series: Genetics In medicine
ISSN: 1098-3600
URI: http://hdl.handle.net/10138/189041
Abstract: Purpose: CHEK2*1100delC is a founder variant in European populations that confers a two-to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.212.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. Conclusion: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.
Subject: breast cancer
Breast Cancer Association Consortium
CHEK2*1100delC
common variants
polygenic risk score
FAMILY-HISTORY
MUTATION
CARRIERS
BRCA2
WOMEN
1184 Genetics, developmental biology, physiology
3122 Cancers
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