Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer

Clendenen, Tess V.; Zeleniuch‐Jacquotte, Anne; Wirgin, Isaac; Koenig, Karen L.; Afanasyeva, Yelena; Lundin, Eva; Arslan, Alan A.; Axelsson, Tomas; Försti, Asta; Hallmans, Göran; Hemminki, Kari; Lenner, Per; Roy, Nirmal Kumar; Shore, Roy E.; Chen, Yu

doi:10.1371/journal.pone.0069367

Cited by 25 publications

(17 citation statements)

References 51 publications

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“…In a large study of Chinese women, Zhang et al (2011) reported that SHBG rs6259 was significantly associated with BC risk in stage I and II combined analyses, in which Global haplotype association P value: 0.0025. the minor allele (A) produced a reduced risk of disease. However, Clendenen et al (2013) and Diergaarde et al (2008) found no association between rs6259 and BC risk, which is in agreement with our findings.…”

Section: Discussionsupporting

confidence: 92%

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women

Pan¹,

Song³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Sex hormones play important roles in breast cancer (BC) development. This study investigated associations between BC risk and hormone-related gene variants in Chinese women. In a cohort of 336 patients with histopathologically confirmed BC and 390 age-matched controls, we genotyped seven single nucleotide polymorphisms (SNPs) in five hormone-related genes: estrogen receptor-α (ESR1), aromatase (CYP19), catechol-O-methyl transferase (COMT), sex hormonebinding globulin (SHBG), and glutathione S-transferase (GSTP1). Among these seven SNPs, the SNPs in GSTP1 rs1695 [A/G; odds ratio (OR): 1.68; 95% confidence interval (CI): 1.23-2.30] and ESR1 rs2046210 (C/T; OR: 1.39; 95%CI = 1.02-1.91) were associated with an increased risk among heterozygote carriers. Homozygotes of minor alleles of CYP19 rs10046 (CC) were associated with a reduced risk of BC with OR: 0.61 (95%CI = 0.39-0.95). In addition, a stratified analysis by menopausal status indicated that the association of the CYP19 polymorphisms (rs10046 and rs700519) with BC risk was mainly evident in premenopausal women, and the association of CYP19 rs700519 with BC risk was significant in women less than 50 years old. Haplotype analysis identified 15 common haplotypes (>1%). The haplotype TGGGGTC was significantly associated with BC risk compared with the reference haplotype CGAGGTC (OR > 1000, P < 0.0001). Our data demonstrate that these ESR1, GSTP1, and CYP19 polymorphisms are associated with risk of BC, and the risk haplotype TGGGGTC could help to identify populations with high susceptibility to BC in Chinese women.

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Section: Discussionsupporting

confidence: 92%

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women

Pan¹,

Song³

et al. 2016

Genet. Mol. Res.

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“…Four studies have shown an elevated risk for breast cancer with the UGT1A1*28 allele in African American (Guillemette et al 2000), Chinese (Adegoke et al 2004), Russian (Shatalova et al 2006) and German (Marie-Genica 2010) women. However, four other studies have shown no association of UGT1A1*28 with breast cancer risk in Taiwanese (Cheng et al 2005), Greek (Tsezou et al 2007), or European American (Guillemette et al 2001) women, or in a mixed population of American and Swedish women (Clendenen et al 2013). Furthermore, one study showed a decreased risk of UGT1A1*28 for breast cancer in Nigerian women (Huo et al 2008).…”

Section: Discussionmentioning

confidence: 97%

Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms

et al. 2016

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Bisphenol-A is a ubiquitous environmental contaminant that is primarily metabolized by glucuronidation and associated with various human diseases including breast cancer. Here we identified UDP-glucuronosyltransferases (UGTs) and genetic polymorphisms responsible for interindividual variability in bisphenol-A glucuronidation in human liver and breast.Hepatic UGTs showing the highest bisphenol-A glucuronidation activity included UGT2B15 and UGT1A9. Relative activity factor normalization indicated that UGT2B15 contributes >80% of activity at bisphenol-A concentrations under 5 µM, while UGT1A9 contributes up to 50% of activity at higher concentrations.Bisphenol-A glucuronidation by liver microsomes (46 donors) ranged from 0.25 to 4.3 nmoles/min/mg protein. Two-fold higher glucuronidation (P = 0.018) was observed in UGT1A9 *22/*22 livers compared with *1/*1 and *1/*22 livers. However, no associations were observed for UGT2B15*2 or UGT1A1*28 genotypes.Bisphenol-A glucuronidation by breast microsomes (15 donors) ranged from <0.2 to 56 fmoles/min/mg protein. Breast mRNA expression of UGTs capable of glucuronidating bisphenol-A was highest for UGT1A1, followed by UGT2B4, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. Bisphenol-A glucuronidation was over 10-fold lower in breast tissues with the UGT1A1*28 allele compared with tissues without this allele (P = 0.006).UGT2B15 and UGT1A9 contribute to glucuronidation variability in liver, while UGT1A1 is important in breast.

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“…In another study, 95 postmenopausal women with stage II–III ER-positive breast cancer were treated with neoadjuvant letrozole, and only rs4646 was associated with a poor response ( P = 0.03) [17]; progression-free survival was reduced in patients carrying (CA/AA) variants compared with those with the reference CC variant [17]. In other recent studies, rs4646 was shown to have no association with breast cancer outcome or risk [18, 20, 22]. In addition, rs700519 SNP variants in exon 7, when compared with the wild-type genotype, have been associated with an increased risk of breast cancer among Hawaiian, Japanese [23], and Korean women [24].…”

Section: Discussionmentioning

confidence: 99%

CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial

Leyland‐Jones

Gray

Abramovitz

et al. 2015

Breast Cancer Res Treat

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To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1–98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34–0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03–1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59–0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07–1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54–0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92–1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.

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Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer

Cited by 25 publications

References 51 publications

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women

Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms

CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial

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