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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 and Jakubowska, Anna, et al. (2012) In Breast Cancer Research and Treatment 136(1). p.295-302
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... (More)

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.

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Adult, Aged, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Chromosomes, Human, Pair 6, Female, Follow-Up Studies, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Humans, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors
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Breast Cancer Research and Treatment
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136
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1
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8 pages
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Springer
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  • scopus:84867845983
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1573-7217
DOI
10.1007/s10549-012-2255-6
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English
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4f8e7676-6506-4ccc-8e20-8ea18041e191
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@article{4f8e7676-6506-4ccc-8e20-8ea18041e191,
  abstract     = {<p>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.</p>},
  author       = {Stevens, Kristen N and Wang, Xianshu and Fredericksen, Zachary and Pankratz, Vernon S and Greene, Mark H and Andrulis, Irene L and Thomassen, Mads and Caligo, Maria and Nathanson, Katherine L and Jakubowska, Anna and Osorio, Ana and Hamann, Ute and Godwin, Andrew K and Stoppa-Lyonnet, Dominique and Southey, Melissa and Buys, Saundra S and Singer, Christian F and Hansen, Thomas V O and Arason, Adalgeir and Offit, Kenneth and Piedmonte, Marion and Montagna, Marco and Imyanitov, Evgeny and Tihomirova, Laima and Sucheston, Lara and Beattie, Mary and Neuhausen, Susan L and Szabo, Csilla I and Simard, Jacques and Spurdle, Amanda B and Healey, Sue and Chen, Xiaoqing and Rebbeck, Timothy R and Easton, Douglas F and Chenevix-Trench, Georgia and Antoniou, Antonis C and Couch, Fergus J and , },
  issn         = {1573-7217},
  keyword      = {Adult,Aged,BRCA1 Protein,BRCA2 Protein,Breast Neoplasms,Chromosomes, Human, Pair 6,Female,Follow-Up Studies,Genetic Association Studies,Genetic Predisposition to Disease,Germ-Line Mutation,Heterozygote,Humans,Middle Aged,Polymorphism, Single Nucleotide,Risk Factors},
  language     = {eng},
  number       = {1},
  pages        = {295--302},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1007/s10549-012-2255-6},
  volume       = {136},
  year         = {2012},
}