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

Taru A Muranen; Dario Greco; Carl Blomqvist; Kristiina Aittomäki; Sofia Khan; Frans Hogervorst; Senno Verhoef; Paul D P Pharoah; Alison M Dunning; Mitul Shah; Robert Luben; Stig E Bojesen; Børge G Nordestgaard; Minouk Schoemaker; Anthony Swerdlow; Montserrat García-Closas; Jonine Figueroa; Thilo Dörk; Natalia V Bogdanova; Per Hall; Jingmei Li; Elza Khusnutdinova; Marina Bermisheva; Vessela Kristensen; Anne-Lise Borresen-Dale; Nbcs Investigators; Julian Peto; Isabel Dos Santos Silva; Fergus J Couch; Janet E Olson; Peter Hillemans; Tjoung-Won Park-Simon; Hiltrud Brauch; Ute Hamann; Barbara Burwinkel; Frederik Marme; Alfons Meindl; Rita K Schmutzler; Angela Cox; Simon S Cross; Elinor J Sawyer; Ian Tomlinson; Diether Lambrechts; Matthieu Moisse; Annika Lindblom; Sara Margolin; Antoinette Hollestelle; John W M Martens; Peter A Fasching; Matthias W Beckmann; Irene L Andrulis; Julia A Knight; kConFab/Aocs Investigators; Hoda Anton-Culver; Argyrios Ziogas; Graham G Giles; Roger L Milne; Hermann Brenner; Volker Arndt; Arto Mannermaa; Veli-Matti Kosma; Jenny Chang-Claude; Anja Rudolph; Peter Devilee; Caroline Seynaeve; John L Hopper; Melissa C Southey; Esther M John; Alice S Whittemore; Manjeet K Bolla; Qin Wang; Kyriaki Michailidou; Joe Dennis; Douglas F Easton; Marjanka K Schmidt; Heli Nevanlinna

doi:10.1038/gim.2016.147

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

Taru A Muranen, Dario Greco, Carl Blomqvist, Kristiina Aittomäki, Sofia Khan, Frans Hogervorst, Senno Verhoef, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Stig E Bojesen, Børge G Nordestgaard, Minouk Schoemaker, Anthony Swerdlow, Montserrat García-Closas, Jonine Figueroa, Thilo Dörk, Natalia V Bogdanova, Per HallJingmei Li, Elza Khusnutdinova, Marina Bermisheva, Vessela Kristensen, Anne-Lise Borresen-Dale, Nbcs Investigators, Julian Peto, Isabel Dos Santos Silva, Fergus J Couch, Janet E Olson, Peter Hillemans, Tjoung-Won Park-Simon, Hiltrud Brauch, Ute Hamann, Barbara Burwinkel, Frederik Marme, Alfons Meindl, Rita K Schmutzler, Angela Cox, Simon S Cross, Elinor J Sawyer, Ian Tomlinson, Diether Lambrechts, Matthieu Moisse, Annika Lindblom, Sara Margolin, Antoinette Hollestelle, John W M Martens, Peter A Fasching, Matthias W Beckmann, Irene L Andrulis, Julia A Knight, kConFab/Aocs Investigators, Hoda Anton-Culver, Argyrios Ziogas, Graham G Giles, Roger L Milne, Hermann Brenner, Volker Arndt, Arto Mannermaa, Veli-Matti Kosma, Jenny Chang-Claude, Anja Rudolph, Peter Devilee, Caroline Seynaeve, John L Hopper, Melissa C Southey, Esther M John, Alice S Whittemore, Manjeet K Bolla, Qin Wang, Kyriaki Michailidou, Joe Dennis, Douglas F Easton, Marjanka K Schmidt, Heli Nevanlinna

Department of Clinical Medicine

36 Citations (Scopus)

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: 1.21-2.09) 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.

Original language	English
Journal	Genetics In Medicine
Volume	19
Issue number	5
Pages (from-to)	599-603
ISSN	1098-3600
DOIs	https://doi.org/10.1038/gim.2016.147
Publication status	Published - 1 May 2017

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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., García-Closas, M., Figueroa, J., Dörk, T., Bogdanova, N. V., ... Nevanlinna, H. (2017). Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics In Medicine, 19(5), 599-603. https://doi.org/10.1038/gim.2016.147

Muranen, TA, Greco, D, Blomqvist, C, Aittomäki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE , Nordestgaard, BG, Schoemaker, M, Swerdlow, A, García-Closas, M, Figueroa, J, Dörk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Investigators, N, Peto, J, Dos Santos Silva, I, Couch, FJ, Olson, JE, Hillemans, P, Park-Simon, T-W, Brauch, H, Hamann, U, Burwinkel, B, Marme, F, Meindl, A, Schmutzler, RK, Cox, A, Cross, SS, Sawyer, EJ, Tomlinson, I, Lambrechts, D, Moisse, M, Lindblom, A, Margolin, S, Hollestelle, A, Martens, JWM, Fasching, PA, Beckmann, MW, Andrulis, IL, Knight, JA, Investigators, KCA, Anton-Culver, H, Ziogas, A, Giles, GG, Milne, RL, Brenner, H, Arndt, V, Mannermaa, A, Kosma, V-M, Chang-Claude, J, Rudolph, A, Devilee, P, Seynaeve, C, Hopper, JL, Southey, MC, John, EM, Whittemore, AS, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Easton, DF, Schmidt, MK & Nevanlinna, H 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

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title = "Genetic modifiers of CHEK2*1100delC-associated breast cancer risk",

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: 1.21-2.09) 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.",

author = "Muranen, {Taru A} and Dario Greco and Carl Blomqvist and Kristiina Aittom{\"a}ki and Sofia Khan and Frans Hogervorst and Senno Verhoef and Pharoah, {Paul D P} and Dunning, {Alison M} and Mitul Shah and Robert Luben and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and Minouk Schoemaker and Anthony Swerdlow and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Thilo D{\"o}rk and Bogdanova, {Natalia V} and Per Hall and Jingmei Li and Elza Khusnutdinova and Marina Bermisheva and Vessela Kristensen and Anne-Lise Borresen-Dale and Nbcs Investigators and Julian Peto and {Dos Santos Silva}, Isabel and Couch, {Fergus J} and Olson, {Janet E} and Peter Hillemans and Tjoung-Won Park-Simon and Hiltrud Brauch and Ute Hamann and Barbara Burwinkel and Frederik Marme and Alfons Meindl and Schmutzler, {Rita K} and Angela Cox and Cross, {Simon S} and Sawyer, {Elinor J} and Ian Tomlinson and Diether Lambrechts and Matthieu Moisse and Annika Lindblom and Sara Margolin and Antoinette Hollestelle and Martens, {John W M} and Fasching, {Peter A} and Beckmann, {Matthias W} and Andrulis, {Irene L} and Knight, {Julia A} and kConFab/Aocs Investigators and Hoda Anton-Culver and Argyrios Ziogas and Giles, {Graham G} and Milne, {Roger L} and Hermann Brenner and Volker Arndt and Arto Mannermaa and Veli-Matti Kosma and Jenny Chang-Claude and Anja Rudolph and Peter Devilee and Caroline Seynaeve and Hopper, {John L} and Southey, {Melissa C} and John, {Esther M} and Whittemore, {Alice S} and Bolla, {Manjeet K} and Qin Wang and Kyriaki Michailidou and Joe Dennis and Easton, {Douglas F} and Schmidt, {Marjanka K} and Heli Nevanlinna",

year = "2017",

month = may,

day = "1",

doi = "10.1038/gim.2016.147",

language = "English",

volume = "19",

pages = "599--603",

journal = "Genetics In Medicine",

issn = "1098-3600",

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number = "5",

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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 - 2017/5/1

Y1 - 2017/5/1

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.

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.

U2 - 10.1038/gim.2016.147

DO - 10.1038/gim.2016.147

M3 - Letter

C2 - 27711073

SN - 1098-3600

VL - 19

SP - 599

EP - 603

JO - Genetics In Medicine

JF - Genetics In Medicine

IS - 5

ER -

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

Abstract

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