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 J Swerdlow, Montserrat García-Closas, Jonine D Figueroa, Thilo Dörk, Natalia V. Bogdanova, Per Hall & 57 others 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 P 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, 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, Breast Cancer Association Consortium, KConFab,AOCS Investigators

Research output: Contribution to journalArticleResearchpeer-review

17 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 languageEnglish
Pages (from-to)599-603
Number of pages5
JournalGenetics in Medicine
Volume19
Issue number5
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

Keywords

  • 1100delC
  • breast cancer
  • Breast Cancer Association Consortium
  • CHEK2
  • common variants
  • polygenic risk score

Cite this

Muranen, T. A., Greco, D., Blomqvist, C., Aittomäki, K., Khan, S., Hogervorst, F., ... KConFab,AOCS Investigators (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, 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 J ; García-Closas, Montserrat ; Figueroa, Jonine D ; 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 P ; 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 ; 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 ; Breast Cancer Association Consortium ; KConFab,AOCS Investigators. / Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk. In: Genetics in Medicine. 2017 ; Vol. 19, No. 5. pp. 599-603.
@article{46bfa1cf3b354384ada83ca12df24536,
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.",
keywords = "1100delC, breast cancer, Breast Cancer Association Consortium, CHEK2, common variants, polygenic risk score",
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 Swerdlow, {Anthony J} and Montserrat Garc{\'i}a-Closas and Figueroa, {Jonine D} 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 Tomlinson, {Ian P} 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 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 and {Breast Cancer Association Consortium} and {KConFab,AOCS Investigators}",
year = "2017",
month = "5",
day = "1",
doi = "10.1038/gim.2016.147",
language = "English",
volume = "19",
pages = "599--603",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "5",

}

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, AJ, García-Closas, M, Figueroa, JD, 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, IP, Lambrechts, D, Moisse, M, Lindblom, A, Margolin, S, Hollestelle, A, Martens, JWM, Fasching, PA, Beckmann, MW, Andrulis, IL, Knight, JA, 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, Breast Cancer Association Consortium & KConFab,AOCS Investigators 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

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 J; García-Closas, Montserrat; Figueroa, Jonine D; 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 P; 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; 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; Breast Cancer Association Consortium; KConFab,AOCS Investigators.

In: Genetics in Medicine, Vol. 19, No. 5, 01.05.2017, p. 599-603.

Research output: Contribution to journalArticleResearchpeer-review

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 J

AU - García-Closas, Montserrat

AU - Figueroa, Jonine D

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 P

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 - 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

AU - Breast Cancer Association Consortium

AU - KConFab,AOCS Investigators

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.

KW - 1100delC

KW - breast cancer

KW - Breast Cancer Association Consortium

KW - CHEK2

KW - common variants

KW - polygenic risk score

UR - http://www.scopus.com/inward/record.url?scp=85021757649&partnerID=8YFLogxK

U2 - 10.1038/gim.2016.147

DO - 10.1038/gim.2016.147

M3 - Article

VL - 19

SP - 599

EP - 603

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 5

ER -

Muranen TA, Greco D, Blomqvist C, Aittomäki K, Khan S, Hogervorst F et al. Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk. Genetics in Medicine. 2017 May 1;19(5):599-603. https://doi.org/10.1038/gim.2016.147