Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. / 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, Børge G; Schoemaker, Minouk; Swerdlow, Anthony; García-Closas, Montserrat; Figueroa, Jonine; Dörk, Thilo; Bogdanova, Natalia V; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Investigators, Nbcs; Peto, Julian; Dos-Santos-Silva, Isabel; 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; Andrulis, Irene L; Knight, Julia A; Investigators, kConFab/Aocs; Anton-Culver, Hoda; Ziogas, Argyrios; Giles, Graham G; Milne, Roger L; Brenner, Hermann; Arndt, Volker; Mannermaa, Arto; Kosma, Veli-Matti; Chang-Claude, Jenny; Rudolph, Anja; Devilee, Peter; Seynaeve, Caroline; Hopper, John L; Southey, Melissa C; John, Esther M; Whittemore, Alice S; Bolla, Manjeet K; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Easton, Douglas F; Schmidt, Marjanka K; Nevanlinna, Heli.
In: GENET MED, Vol. 19, No. 5, 05.2017, p. 599-603.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
AU - Muranen, Taru A
AU - Greco, Dario
AU - Blomqvist, Carl
AU - Aittomäki, Kristiina
AU - Khan, Sofia
AU - Hogervorst, Frans
AU - Verhoef, Senno
AU - Pharoah, Paul D P
AU - Dunning, Alison M
AU - Shah, Mitul
AU - Luben, Robert
AU - Bojesen, Stig E
AU - Nordestgaard, Børge G
AU - Schoemaker, Minouk
AU - Swerdlow, Anthony
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Dörk, Thilo
AU - Bogdanova, Natalia V
AU - Hall, Per
AU - Li, Jingmei
AU - Khusnutdinova, Elza
AU - Bermisheva, Marina
AU - Kristensen, Vessela
AU - Borresen-Dale, Anne-Lise
AU - Investigators, Nbcs
AU - Peto, Julian
AU - Dos-Santos-Silva, Isabel
AU - Couch, Fergus J
AU - Olson, Janet E
AU - Hillemans, Peter
AU - Park-Simon, Tjoung-Won
AU - Brauch, Hiltrud
AU - Hamann, Ute
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Meindl, Alfons
AU - Schmutzler, Rita K
AU - Cox, Angela
AU - Cross, Simon S
AU - Sawyer, Elinor J
AU - Tomlinson, Ian
AU - Lambrechts, Diether
AU - Moisse, Matthieu
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Hollestelle, Antoinette
AU - Martens, John W M
AU - Fasching, Peter A
AU - Beckmann, Matthias W
AU - Andrulis, Irene L
AU - Knight, Julia A
AU - Investigators, kConFab/Aocs
AU - Anton-Culver, Hoda
AU - Ziogas, Argyrios
AU - Giles, Graham G
AU - Milne, Roger L
AU - Brenner, Hermann
AU - Arndt, Volker
AU - Mannermaa, Arto
AU - Kosma, Veli-Matti
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Devilee, Peter
AU - Seynaeve, Caroline
AU - Hopper, John L
AU - Southey, Melissa C
AU - John, Esther M
AU - Whittemore, Alice S
AU - Bolla, Manjeet K
AU - Wang, Qin
AU - Michailidou, Kyriaki
AU - Dennis, Joe
AU - Easton, Douglas F
AU - Schmidt, Marjanka K
AU - Nevanlinna, Heli
PY - 2017/5
Y1 - 2017/5
N2 - 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: 1.21-2.09) 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.Genet Med advance online publication 06 October 2016.
AB - 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: 1.21-2.09) 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.Genet Med advance online publication 06 October 2016.
KW - Journal Article
U2 - 10.1038/gim.2016.147
DO - 10.1038/gim.2016.147
M3 - SCORING: Journal article
C2 - 27711073
VL - 19
SP - 599
EP - 603
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 5
ER -