Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics
Copyright policy )Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics
A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
- Amsterdam UMC Netherlands
- University of Copenhagen Denmark
- Harvard University United States
- Universität Hamburg Germany
- University of Pisa Italy
FGFR2 protein, genetic association, cancer risk, QH426-470, progesterone receptor, Linkage Disequilibrium, genetic heterogeneity, Trinucleotide Repeats, single nucleotide polymorphism, genetic variability, middle aged, Odds Ratio, genetics, cancer survival, EMC MGC-02-96-01, risk, breast tumor, fibroblast growth factor receptor 2, Microfilament Proteins, allele, article, High Mobility Group Proteins, Middle Aged, actin binding protein, cancer susceptibility, Europe, female, chromosome 8q, Female, Receptors, Progesterone, cancer invasion, estrogen receptor, Research Article, Chromosomes, Human, Pair 8, 570, mitogen activated protein kinase kinase kinase 1, gene locus, overall survival, cancer genetics, 610, MAP Kinase Kinase Kinase 1, Breast Neoplasms, Polymorphism, Single Nucleotide, breast cancer, SDG 3 - Good Health and Well-being, chromosome 8, Genetics, Humans, controlled study, Genetic Predisposition to Disease, human, Receptor, Fibroblast Growth Factor, Type 2, MAP3K1 protein, Breast Neoplasms; Case-Control Studies; Chromosomes, Human, Pair 8; Female; Humans; Linkage Disequilibrium; MAP Kinase Kinase Kinase 1; Microfilament Proteins; Middle Aged; Odds Ratio; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Progesterone; Trinucleotide Repeats; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Ecology, Evolution, Behavior and Systematics; Molecular Biology; Genetics; Genetics (clinical); Cancer Research, Asian, breast carcinogenesis, TNRC9 protein, LSP1 protein, case control study, major clinical study, clinical feature, gene linkage disequilibrium, EMC MM-01-39-02, Case-Control Studies, Trans-Activators, pathology, prognosis, EMC MM-03-86-01, Apoptosis Regulatory Proteins, genetic predisposition, genetic susceptibility
FGFR2 protein, genetic association, cancer risk, QH426-470, progesterone receptor, Linkage Disequilibrium, genetic heterogeneity, Trinucleotide Repeats, single nucleotide polymorphism, genetic variability, middle aged, Odds Ratio, genetics, cancer survival, EMC MGC-02-96-01, risk, breast tumor, fibroblast growth factor receptor 2, Microfilament Proteins, allele, article, High Mobility Group Proteins, Middle Aged, actin binding protein, cancer susceptibility, Europe, female, chromosome 8q, Female, Receptors, Progesterone, cancer invasion, estrogen receptor, Research Article, Chromosomes, Human, Pair 8, 570, mitogen activated protein kinase kinase kinase 1, gene locus, overall survival, cancer genetics, 610, MAP Kinase Kinase Kinase 1, Breast Neoplasms, Polymorphism, Single Nucleotide, breast cancer, SDG 3 - Good Health and Well-being, chromosome 8, Genetics, Humans, controlled study, Genetic Predisposition to Disease, human, Receptor, Fibroblast Growth Factor, Type 2, MAP3K1 protein, Breast Neoplasms; Case-Control Studies; Chromosomes, Human, Pair 8; Female; Humans; Linkage Disequilibrium; MAP Kinase Kinase Kinase 1; Microfilament Proteins; Middle Aged; Odds Ratio; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Progesterone; Trinucleotide Repeats; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Ecology, Evolution, Behavior and Systematics; Molecular Biology; Genetics; Genetics (clinical); Cancer Research, Asian, breast carcinogenesis, TNRC9 protein, LSP1 protein, case control study, major clinical study, clinical feature, gene linkage disequilibrium, EMC MM-01-39-02, Case-Control Studies, Trans-Activators, pathology, prognosis, EMC MM-03-86-01, Apoptosis Regulatory Proteins, genetic predisposition, genetic susceptibility
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