Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

Mia M Gaudet; Tomas Kirchhoff; Todd Green; Joseph Vijai; Joshua M Korn; Candace Guiducci; Ayellet V Segrè; Kate McGee; Lesley McGuffog; Christiana Kartsonaki; Jonathan Morrison; Sue Healey; Olga M Sinilnikova; Dominique Stoppa-Lyonnet; Sylvie Mazoyer; Marion Gauthier-Villars; Hagay Sobol; Michel Longy; Marc Frenay; null GEMO Study Collaborators; Frans B L Hogervorst; Matti A Rookus; J Margriet Collée; Nicoline Hoogerbrugge; Kees E P van Roozendaal; Marion Piedmonte; Wendy Rubinstein; Stacy Nerenstone; Linda Van Le; Stephanie V Blank; Trinidad Caldés; Miguel de la Hoya; Heli Nevanlinna; Kristiina Aittomäki; Conxi Lazaro; Ignacio Blanco; Adalgeir Arason; Oskar T Johannsson; Rosa B Barkardottir; Peter Devilee; Olofunmilayo I Olopade; Susan L Neuhausen; Xianshu Wang; Zachary S Fredericksen; Paolo Peterlongo; Siranoush Manoukian; Monica Barile; Alessandra Viel; Thomas V Overeem Hansen; Finn C Nielsen; HEBON Study Collaborators

doi:10.1371/journal.pgen.1001183

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study CollaboratorsFrans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Thomas V Overeem Hansen, Finn C Nielsen, HEBON Study Collaborators

75 Citationer (Scopus)

Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10^-5 and 39 SNPs had p-values<10^-4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p=3:8×10^-5) and for rs311499 was 0.72 (95% CI 0.61-0.85, p=6:6-×10^-5). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p=1:2×10^-8). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Originalsprog	Engelsk
Tidsskrift	P L o S Genetics
Vol/bind	6
Udgave nummer	10
Sider (fra-til)	e1001183
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1001183
Status	Udgivet - 1 okt. 2010

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10.1371/journal.pgen.1001183

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Gaudet, M. M., Kirchhoff, T., Green, T., Vijai, J., Korn, J. M., Guiducci, C., Segrè, A. V., McGee, K., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O. M., Stoppa-Lyonnet, D., Mazoyer, S., Gauthier-Villars, M., Sobol, H., Longy, M., Frenay, M., ... HEBON Study Collaborators (2010). Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. P L o S Genetics, 6(10), e1001183. https://doi.org/10.1371/journal.pgen.1001183

Gaudet, MM, Kirchhoff, T, Green, T, Vijai, J, Korn, JM, Guiducci, C, Segrè, AV, McGee, K, McGuffog, L, Kartsonaki, C, Morrison, J, Healey, S, Sinilnikova, OM, Stoppa-Lyonnet, D, Mazoyer, S, Gauthier-Villars, M, Sobol, H, Longy, M, Frenay, M, GEMO Study Collaborators, Hogervorst, FBL, Rookus, MA, Collée, JM, Hoogerbrugge, N, van Roozendaal, KEP, Piedmonte, M, Rubinstein, W, Nerenstone, S, Van Le, L, Blank, SV, Caldés, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Lazaro, C, Blanco, I, Arason, A, Johannsson, OT, Barkardottir, RB, Devilee, P, Olopade, OI, Neuhausen, SL, Wang, X, Fredericksen, ZS, Peterlongo, P, Manoukian, S, Barile, M, Viel, A, Overeem Hansen, TV , Nielsen, FC & HEBON Study Collaborators 2010, 'Common genetic variants and modification of penetrance of BRCA2-associated breast cancer', P L o S Genetics, bind 6, nr. 10, s. e1001183. https://doi.org/10.1371/journal.pgen.1001183

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title = "Common genetic variants and modification of penetrance of BRCA2-associated breast cancer",

abstract = "The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10-5 and 39 SNPs had p-values<10-4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p=3:8×10-5) and for rs311499 was 0.72 (95% CI 0.61-0.85, p=6:6-×10-5). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p=1:2×10-8). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.",

author = "Gaudet, {Mia M} and Tomas Kirchhoff and Todd Green and Joseph Vijai and Korn, {Joshua M} and Candace Guiducci and Segr{\`e}, {Ayellet V} and Kate McGee and Lesley McGuffog and Christiana Kartsonaki and Jonathan Morrison and Sue Healey and Sinilnikova, {Olga M} and Dominique Stoppa-Lyonnet and Sylvie Mazoyer and Marion Gauthier-Villars and Hagay Sobol and Michel Longy and Marc Frenay and {GEMO Study Collaborators} and Hogervorst, {Frans B L} and Rookus, {Matti A} and Coll{\'e}e, {J Margriet} and Nicoline Hoogerbrugge and {van Roozendaal}, {Kees E P} and Marion Piedmonte and Wendy Rubinstein and Stacy Nerenstone and {Van Le}, Linda and Blank, {Stephanie V} and Trinidad Cald{\'e}s and {de la Hoya}, Miguel and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Conxi Lazaro and Ignacio Blanco and Adalgeir Arason and Johannsson, {Oskar T} and Barkardottir, {Rosa B} and Peter Devilee and Olopade, {Olofunmilayo I} and Neuhausen, {Susan L} and Xianshu Wang and Fredericksen, {Zachary S} and Paolo Peterlongo and Siranoush Manoukian and Monica Barile and Alessandra Viel and {Overeem Hansen}, {Thomas V} and Nielsen, {Finn C} and Nielsen, {Finn Cilius}",

year = "2010",

month = oct,

day = "1",

doi = "10.1371/journal.pgen.1001183",

language = "English",

volume = "6",

pages = "e1001183",

journal = "P L o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

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TY - JOUR

T1 - Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

AU - Gaudet, Mia M

AU - Kirchhoff, Tomas

AU - Green, Todd

AU - Vijai, Joseph

AU - Korn, Joshua M

AU - Guiducci, Candace

AU - Segrè, Ayellet V

AU - McGee, Kate

AU - McGuffog, Lesley

AU - Kartsonaki, Christiana

AU - Morrison, Jonathan

AU - Healey, Sue

AU - Sinilnikova, Olga M

AU - Stoppa-Lyonnet, Dominique

AU - Mazoyer, Sylvie

AU - Gauthier-Villars, Marion

AU - Sobol, Hagay

AU - Longy, Michel

AU - Frenay, Marc

AU - GEMO Study Collaborators, null

AU - Hogervorst, Frans B L

AU - Rookus, Matti A

AU - Collée, J Margriet

AU - Hoogerbrugge, Nicoline

AU - van Roozendaal, Kees E P

AU - Piedmonte, Marion

AU - Rubinstein, Wendy

AU - Nerenstone, Stacy

AU - Van Le, Linda

AU - Blank, Stephanie V

AU - Caldés, Trinidad

AU - de la Hoya, Miguel

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Arason, Adalgeir

AU - Johannsson, Oskar T

AU - Barkardottir, Rosa B

AU - Devilee, Peter

AU - Olopade, Olofunmilayo I

AU - Neuhausen, Susan L

AU - Wang, Xianshu

AU - Fredericksen, Zachary S

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Barile, Monica

AU - Viel, Alessandra

AU - Overeem Hansen, Thomas V

AU - Nielsen, Finn C

AU - HEBON Study Collaborators

PY - 2010/10/1

Y1 - 2010/10/1

N2 - The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10-5 and 39 SNPs had p-values<10-4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p=3:8×10-5) and for rs311499 was 0.72 (95% CI 0.61-0.85, p=6:6-×10-5). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p=1:2×10-8). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

AB - The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10-5 and 39 SNPs had p-values<10-4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p=3:8×10-5) and for rs311499 was 0.72 (95% CI 0.61-0.85, p=6:6-×10-5). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p=1:2×10-8). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

U2 - 10.1371/journal.pgen.1001183

DO - 10.1371/journal.pgen.1001183

M3 - Journal article

SN - 1553-7390

VL - 6

SP - e1001183

JO - P L o S Genetics

JF - P L o S Genetics

IS - 10

ER -

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

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