Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. / Kuchenbaecker, Karoline B; Loman, Niklas; Borg, Åke; Ehrencrona, Hans; Antoniou, Antonis C.; Olsson, Håkan (Contributor); Jernström, Helena (Contributor); Henriksson, Karin (Contributor); Harbst, Katja (Contributor); Soller, Maria (Contributor); Kristoffersson, Ulf (Contributor); EMBRACE Study.

In: Breast Cancer Research, Vol. 16, No. 6, 3416, 31.12.2014, p. 1-27.

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T1 - Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

AU - Kuchenbaecker, Karoline B

AU - Loman, Niklas

AU - Borg, Åke

AU - Ehrencrona, Hans

AU - Antoniou, Antonis C.

AU - EMBRACE Study

A2 - Olsson, Håkan

A2 - Jernström, Helena

A2 - Henriksson, Karin

A2 - Harbst, Katja

A2 - Soller, Maria

A2 - Kristoffersson, Ulf

PY - 2014/12/31

Y1 - 2014/12/31

N2 - INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

AB - INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

KW - Adult

KW - Aged

KW - Alleles

KW - Breast Neoplasms/genetics

KW - Carcinoma/genetics

KW - Carcinoma, Ductal, Breast/genetics

KW - Carcinoma, Lobular/genetics

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Middle Aged

KW - Neoplasm Grading

KW - Neoplasm Staging

KW - Receptor, ErbB-2/metabolism

KW - Receptors, Estrogen/metabolism

KW - Receptors, Progesterone/metabolism

U2 - 10.1186/s13058-014-0492-9

DO - 10.1186/s13058-014-0492-9

M3 - Article

C2 - 25919761

VL - 16

SP - 1

EP - 27

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 6

M1 - 3416

ER -