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

Breast Cancer Association Consortium, KConFab,AOCS Investigators

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)599-603
Number of pages5
JournalGenetics in Medicine
Volume19
Issue number5
DOIs
StatePublished - May 1 2017

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Breast Neoplasms
Odds Ratio
Population
Epidemiologic Studies
Genotype
Guidelines

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Breast Cancer Association Consortium, & 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

Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk. / 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 journalArticle

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
Breast Cancer Association Consortium, KConFab,AOCS Investigators. 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
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.
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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 = "{Breast Cancer Association Consortium} and {KConFab,AOCS Investigators} and 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 Borresen-Dale, {Anne Lise} and Nbcs Investigators and Julian Peto and {Dos Santos Silva}, Isabel and Couch, {Fergus J} and Olson, {Janet E} and Peter Hillemans and Park-Simon, {Tjoung Won} 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.}",
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TY - JOUR

T1 - Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk

AU - Breast Cancer Association Consortium

AU - KConFab,AOCS Investigators

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.

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

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DO - 10.1038/gim.2016.147

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