Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

Kristen N Stevens, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Mark H Greene, Irene L Andrulis, Mads Thomassen, Maria Caligo, Katherine L Nathanson, Anna Jakubowska, Ana Osorio, Ute Hamann, Andrew K Godwin, Dominique Stoppa-Lyonnet, Melissa Southey, Saundra S Buys, Christian F Singer, Thomas V O Hansen, Adalgeir Arason, Kenneth Offit & 18 others Marion Piedmonte, Marco Montagna, Evgeny Imyanitov, Laima Tihomirova, Lara Sucheston, Mary Beattie, Susan L Neuhausen, Csilla I Szabo, Jacques Simard, Amanda B Spurdle, Sue Healey, Xiaoqing Chen, Timothy R Rebbeck, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Fergus J Couch, Swedish Breast Cancer Study, Sweden (SWE-BRCA)

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
Original languageEnglish
JournalBreast Cancer Research and Treatment
Volume136
Issue number1
Pages (from-to)295-302
Number of pages8
ISSN0167-6806
DOIs
Publication statusPublished - 2012

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Mutation
Genome-Wide Association Study
Confidence Intervals
Germ-Line Mutation
Ovarian Neoplasms
Research Personnel
Population

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Stevens, K. N., Wang, X., Fredericksen, Z., Pankratz, V. S., Greene, M. H., Andrulis, I. L., ... Swedish Breast Cancer Study, Sweden (SWE-BRCA) (2012). Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers. Breast Cancer Research and Treatment, 136(1), 295-302. https://doi.org/10.1007/s10549-012-2255-6
Stevens, Kristen N ; Wang, Xianshu ; Fredericksen, Zachary ; Pankratz, Vernon S ; Greene, Mark H ; Andrulis, Irene L ; Thomassen, Mads ; Caligo, Maria ; Nathanson, Katherine L ; Jakubowska, Anna ; Osorio, Ana ; Hamann, Ute ; Godwin, Andrew K ; Stoppa-Lyonnet, Dominique ; Southey, Melissa ; Buys, Saundra S ; Singer, Christian F ; Hansen, Thomas V O ; Arason, Adalgeir ; Offit, Kenneth ; Piedmonte, Marion ; Montagna, Marco ; Imyanitov, Evgeny ; Tihomirova, Laima ; Sucheston, Lara ; Beattie, Mary ; Neuhausen, Susan L ; Szabo, Csilla I ; Simard, Jacques ; Spurdle, Amanda B ; Healey, Sue ; Chen, Xiaoqing ; Rebbeck, Timothy R ; Easton, Douglas F ; Chenevix-Trench, Georgia ; Antoniou, Antonis C ; Couch, Fergus J ; Swedish Breast Cancer Study, Sweden (SWE-BRCA). / Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers. In: Breast Cancer Research and Treatment. 2012 ; Vol. 136, No. 1. pp. 295-302.
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abstract = "Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 {\%} confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 {\%} CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.",
author = "Stevens, {Kristen N} and Xianshu Wang and Zachary Fredericksen and Pankratz, {Vernon S} and Greene, {Mark H} and Andrulis, {Irene L} and Mads Thomassen and Maria Caligo and Nathanson, {Katherine L} and Anna Jakubowska and Ana Osorio and Ute Hamann and Godwin, {Andrew K} and Dominique Stoppa-Lyonnet and Melissa Southey and Buys, {Saundra S} and Singer, {Christian F} and Hansen, {Thomas V O} and Adalgeir Arason and Kenneth Offit and Marion Piedmonte and Marco Montagna and Evgeny Imyanitov and Laima Tihomirova and Lara Sucheston and Mary Beattie and Neuhausen, {Susan L} and Szabo, {Csilla I} and Jacques Simard and Spurdle, {Amanda B} and Sue Healey and Xiaoqing Chen and Rebbeck, {Timothy R} and Easton, {Douglas F} and Georgia Chenevix-Trench and Antoniou, {Antonis C} and Couch, {Fergus J} and {Swedish Breast Cancer Study, Sweden (SWE-BRCA)}",
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Stevens, KN, Wang, X, Fredericksen, Z, Pankratz, VS, Greene, MH, Andrulis, IL, Thomassen, M, Caligo, M, Nathanson, KL, Jakubowska, A, Osorio, A, Hamann, U, Godwin, AK, Stoppa-Lyonnet, D, Southey, M, Buys, SS, Singer, CF, Hansen, TVO, Arason, A, Offit, K, Piedmonte, M, Montagna, M, Imyanitov, E, Tihomirova, L, Sucheston, L, Beattie, M, Neuhausen, SL, Szabo, CI, Simard, J, Spurdle, AB, Healey, S, Chen, X, Rebbeck, TR, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Couch, FJ & Swedish Breast Cancer Study, Sweden (SWE-BRCA) 2012, 'Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers', Breast Cancer Research and Treatment, vol. 136, no. 1, pp. 295-302. https://doi.org/10.1007/s10549-012-2255-6

Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers. / Stevens, Kristen N; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Greene, Mark H; Andrulis, Irene L; Thomassen, Mads; Caligo, Maria; Nathanson, Katherine L; Jakubowska, Anna; Osorio, Ana; Hamann, Ute; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Southey, Melissa; Buys, Saundra S; Singer, Christian F; Hansen, Thomas V O; Arason, Adalgeir; Offit, Kenneth; Piedmonte, Marion; Montagna, Marco; Imyanitov, Evgeny; Tihomirova, Laima; Sucheston, Lara; Beattie, Mary; Neuhausen, Susan L; Szabo, Csilla I; Simard, Jacques; Spurdle, Amanda B; Healey, Sue; Chen, Xiaoqing; Rebbeck, Timothy R; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Couch, Fergus J; Swedish Breast Cancer Study, Sweden (SWE-BRCA).

In: Breast Cancer Research and Treatment, Vol. 136, No. 1, 2012, p. 295-302.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

AU - Stevens, Kristen N

AU - Wang, Xianshu

AU - Fredericksen, Zachary

AU - Pankratz, Vernon S

AU - Greene, Mark H

AU - Andrulis, Irene L

AU - Thomassen, Mads

AU - Caligo, Maria

AU - Nathanson, Katherine L

AU - Jakubowska, Anna

AU - Osorio, Ana

AU - Hamann, Ute

AU - Godwin, Andrew K

AU - Stoppa-Lyonnet, Dominique

AU - Southey, Melissa

AU - Buys, Saundra S

AU - Singer, Christian F

AU - Hansen, Thomas V O

AU - Arason, Adalgeir

AU - Offit, Kenneth

AU - Piedmonte, Marion

AU - Montagna, Marco

AU - Imyanitov, Evgeny

AU - Tihomirova, Laima

AU - Sucheston, Lara

AU - Beattie, Mary

AU - Neuhausen, Susan L

AU - Szabo, Csilla I

AU - Simard, Jacques

AU - Spurdle, Amanda B

AU - Healey, Sue

AU - Chen, Xiaoqing

AU - Rebbeck, Timothy R

AU - Easton, Douglas F

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C

AU - Couch, Fergus J

AU - Swedish Breast Cancer Study, Sweden (SWE-BRCA)

PY - 2012

Y1 - 2012

N2 - Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

AB - Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

U2 - 10.1007/s10549-012-2255-6

DO - 10.1007/s10549-012-2255-6

M3 - Journal article

VL - 136

SP - 295

EP - 302

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -