Genetic variation in the androgen estrogen conversion pathway in relation to breast cancer prognosticators

Abstract

Purpose:Genetic variation in the androgen-to-estrogen conversion pathway has been shown to be associated with risk of breast cancer, and in particular with Estrogen Receptor (ER) positive tumours. We aimed at studying how the genetic alterations, which have been identified for risk, are associated with breast cancer prognosticators, with a prior hypothesis that, in general, hormone related breast cancers have a better prognosis than non-hormone related breast cancers. Methods:Association between tagging SNPs in genes involved in estrogen metabolism and patient's lymph node status, tumour size and histological grade, were estimated in a sample of 1569 Swedish breast cancer patients. Results:Polymorphisms in CYP19A1, which have previously been linked to breast cancer risk, are shown to be associated with breast cancer prognosticators. The strongest association was observed for rs4646, with histological grade. The common allele of rs4646, which has been associated with increased breast cancer risk, was associated with low histological grade and small tumour size (p=0.001 and 0.015; 1-sided, respectively). We also found evidence that SNP rs7167936 is associated with histological grade and tumour size (p=0.010 and 0.005; 1-sided, respectively). We show that rs4646 and rs7167936 are associated with histological grade even amongst only ER-positive tumours (p=0.008 and 0.011; 1-sided, respectively). Conclusions:Our results provide new evidence that CYP19A1 is involved in both breast cancer risk and prognosis.3

Androgen receptor genotypes predict response to endocrine treatment in breast cancer patients

“…Since AI response may be dependent on the CYP19A1 SNP rs4646 (Colomer et al , 2008; Darabi et al , 2011), the rs4646 allele distribution was assessed. The rs4646 distribution did not significantly differ between groups A and B (results not shown).…”

“…In contrast, adjuvant AI treatment had no effect on breast cancer-free survival in this group of patients, a finding suggestive of AI resistance. Therefore, we analysed the allele distribution of the CYP19A1 rs4646, which has been suggested to be involved in AI resistance (Colomer et al , 2008; Darabi et al , 2011). The difference in AI and TAM treatment response in group B was independent of the CYP19A1 rs4646 variant.…”

Associations between Aromatase CYP19 rs10046 Polymorphism and Breast Cancer Risk: From a Case-Control to a Meta-Analysis of 20,098 Subjects

“…There are some studies about polymorphisms in linkage disequilibrium with rs10046 which describe a significant association with efficacy of the aromatase inhibitor letrozole in patients with breast cancer, as is the case for rs700158 [42] and rs4646 [23], [24]. The latter SNP has also been reported to be associated with HER2 status of tumors [9], circulating steroid hormones [35] and histological grade and tumor size in postmenopausal women [35], [43]. Haiman et al reported a significant relationship between this SNP and circulating estrogen levels among postmenopausal women.…”

“…Additionally, rs10046 has been related to altered disease free survival in the subgroup of pre-menopausal breast cancer patients [9]. Polymorphisms in linkage disequilibrium with rs10046, as in the case of rs4664, rs700518 and rs700519, has been associated with variable efficacy of treatments [23], [24], [42] and breast cancer survival [43], [44].…”

Single- and Multi-Locus Association Tests Incorporating Phenotype Heterogeneity

“…The p value for the Cochran-Armitage trend test of association (with 21 breast cancer risk) for this SNP was 0.008 in our study [12] . We recently found this SNP to also be associated with both tumour grade and tumour size amongst the cases in CAHRES [20] , with p values of 0.002 and 0.030, based on fitting an ordinal logistic model and a linear regression model, respectively.…”