Dataset Information

Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study.

ABSTRACT: Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.

SUBMITTER: Brooks JD

PROVIDER: S-EPMC3612453 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study.

Brooks Jennifer D JD Teraoka Sharon N SN Malone Kathleen E KE Haile Robert W RW Bernstein Leslie L Lynch Charles F CF Mellemkjær Lene L Duggan David J DJ Reiner Anne S AS Concannon Patrick P Schiermeyer Katherine K Lewinger Juan Pablo JP Bernstein Jonine L JL Figueiredo Jane C JC

International journal of molecular epidemiology and genetics 20130318 1

Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen ...[more]

PMID: 23565321

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Project description:BackgroundTamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.MethodsGermline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.ResultsAmong women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02).ConclusionThis study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

Project description:Background:Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown. Methods:Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates. Results:Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI?=?6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI?=?1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history. Conclusions:Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.

Project description:Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.

Project description:BackgroundKIAA genes identified in the Kazusa cDNA-sequencing project may play important roles in biological processes and are involved in carcinogenesis of many cancers. Genetic variants of KIAA genes are implicated in the abnormal expression of these genes and are linked to susceptibility of several human complex diseases.MethodsThe differentially expressed KIAA genes were screened and identified in The Cancer Genome Atlas (TCGA) database of breast cancer. A total of 48 variants located in the 28 KIAA genes were selected to investigate the associations between polymorphism and breast cancer in 1,032 cases and 1,063 cancer-free controls in a Chinese population.ResultsTwo coding variants, which included a SNP rs2306369 in KIAA1109 and a SNP rs1205434 in KIAA1755, were identified to be associated with the incidences of breast cancer. Logistic regression analysis showed that the SNP rs2306369 G allele was associated with a decreased risk of breast cancer (additive model: OR =0.81, 95% CI: 0.66-0.99, P=0.038), whereas the SNP rs1205434 A allele was involved with a higher risk of breast cancer (additive model: OR =1.19, 95% CI: 1.02-1.38, P= 0.025). Further stratified analysis revealed that the SNP rs1205434 showed a significant difference for age at menarche strata (heterogeneity test P=0.009). Multiplicative interaction analysis indicated that there was positive multiplicative interaction between the SNP rs1205434 and menarche age (OR =1.09, 95% CI: 1.01-1.17, P=0.036). Additionally, expression quantitative trait loci analysis revealed that the SNP rs1205434 A allele could decrease the KIAA1755 expression in the Genotype-Tissue Expression (GTEx) database (P=0.002). The Kaplan-Meier plotter showed that breast cancer patients with high KIAA1755 expression have significantly better outcomes than those with low levels of expression (HR =0.84, 95% CI: 0.72-0.99, P=0.033).ConclusionsThe results indicate that the genetic variants (rs2306369 and rs1205434) in the coding region of KIAA1109 and KIAA1755 respectively may affect Chinese females' breast cancer susceptibility and act as potential predictive biomarkers for breast cancer.

Dataset Information

Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study.

Publications

Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study.

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