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

NBCS Investigators; 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; 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; Arto Mannermaa; Veli-Matti Kosma

doi:10.1038/gim.2016.147

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

NBCS Investigators
, 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, 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, Arto Mannermaa, Veli-Matti Kosma

Research output: Contribution to journal › Article › Scientific › peer-review

72 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.Genet Med advance online publication 06 October 2016.

Original language	English
Pages (from-to)	599-603
Number of pages	5
Journal	Genetics in Medicine
Volume	19
Issue number	5
DOIs	https://doi.org/10.1038/gim.2016.147
Publication status	Published - May 2017
Externally published	Yes
Publication type	A1 Journal article-refereed

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Breast Neoplasms/genetics
Checkpoint Kinase 2/genetics
Female
Genes, Modifier
Genetic Predisposition to Disease
Humans
Odds Ratio
Penetrance
Sequence Deletion

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10.1038/gim.2016.147

Cite this

NBCS Investigators, 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., ... Kosma, V.-M. (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

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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.Genet Med advance online publication 06 October 2016.",

keywords = "Breast Neoplasms/genetics, Checkpoint Kinase 2/genetics, Female, Genes, Modifier, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Sequence Deletion",

author = "\{NBCS 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 Anne-Lise Borresen-Dale 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 Arto Mannermaa and Veli-Matti Kosma",

year = "2017",

month = may,

doi = "10.1038/gim.2016.147",

language = "English",

volume = "19",

pages = "599--603",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "5",

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NBCS Investigators, 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, 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, Mannermaa, A & Kosma, V-M 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

TY - JOUR

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

AU - NBCS 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 - 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 - Mannermaa, Arto

AU - Kosma, Veli-Matti

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 - Breast Neoplasms/genetics

KW - Checkpoint Kinase 2/genetics

KW - Female

KW - Genes, Modifier

KW - Genetic Predisposition to Disease

KW - Humans

KW - Odds Ratio

KW - Penetrance

KW - Sequence Deletion

U2 - 10.1038/gim.2016.147

DO - 10.1038/gim.2016.147

M3 - Article

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

UN SDGs

Keywords

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