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The Association of CYP19A1 Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can CYP19A1 Variants Be Used to Predict Treatment Efficacy?

ABSTRACT: After menopause, estradiol is primarily synthesized in peripheral tissues by the enzyme aromatase, encoded by CYP19A1. CYP19A1 variation associates with circulating estradiol in postmenopausal women and this variation is best represented by the intronic variant rs727479. This variation appears to have pleiotropic effects as it also associates with endometrial cancer risk. Indeed, estradiol plays an important role in the development of breast and endometrial cancer. Aromatase inhibitor (AI) drugs are used in the treatment of both diseases, however, response rates for AIs are low and there is currently no way to identify breast or endometrial cancer patients who are more likely to receive a clinical benefit. Multiple studies have proposed that genetic variation in CYP19A1 will have effects on AI efficacy: eight candidate variant studies of sample size greater than 50 describe associations between CYP19A1 variation and the outcome of patients treated with AIs. Nominally significant associations with patient outcome were reported for several variants, including rs727479. However, only an association between rs4646 and time to progression was replicated in an independent study. Moreover, rs4646 is also the only variant that has an association with patient outcome that passes a multiple testing threshold and this variant is in linkage disequilibrium with rs727479, supporting the hypothesis that associations with patient outcome may be driven through the effects on circulating estradiol. Despite this preliminary evidence, well phenotyped and comprehensively genotyped patient sets need to be studied before conclusions can be drawn about the effects of CYP19A1 variation on AI efficacy.

SUBMITTER: Glubb DM

PROVIDER: S-EPMC5403944 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Association of CYP19A1 Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can CYP19A1 Variants Be Used to Predict Treatment Efficacy?

Glubb Dylan M DM O'Mara Tracy A TA Shamsani Jannah J Spurdle Amanda B AB

Frontiers in pharmacology 20170425

After menopause, estradiol is primarily synthesized in peripheral tissues by the enzyme aromatase, encoded by CYP19A1. CYP19A1 variation associates with circulating estradiol in postmenopausal women and this variation is best represented by the intronic variant rs727479. This variation appears to have pleiotropic effects as it also associates with endometrial cancer risk. Indeed, estradiol plays an important role in the development of breast and endometrial cancer. Aromatase inhibi ...[more]

PMID: 28487654

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Project description:BACKGROUND: Aromatase deficiency is a rare, autosomal recessive disorder of which there are approximately twenty four case reports. The aromatase enzyme is crucial in the biosynthesis of oestrogens from androgens. The phenotype of aromatase deficiency therefore is the result of androgen excess and oestrogen deficiency in the absence of normal aromatase activity. We report the first case of aromatase deficiency diagnosed in a female adult, at the age of 32 years, due to a novel duplication in the aromatase gene. CASE PRESENTATION: A 32 year old Indian woman presented with a history of gender assignment difficulties at birth, lack of pubertal development, osteopaenia with fracture and tall stature. She had central obesity, impaired fasting glucose and borderline hypertension. Past examinations had revealed partial fusion of urethra and vagina, hypoplastic uterus and streak ovaries. The ovaries had been excised due to malignant risk after an initial clinical diagnosis of Turner's syndrome with Y mosaicism. Oestrogen replacement commenced shortly after her fracture, in adulthood. After reassessment, aromatase deficiency was diagnosed. Sequencing of the coding exons of the aromatase (CYP19A1; OMIM 109710) gene revealed a novel 27-base duplication in exon 8 (p.Ala306_Ser314dup). This duplication, occurring within the aromatase ?-helix, would be likely to disrupt substrate (androgen) and cofactor (protoporphyrin IX) binding, resulting in a lack of oestrogen synthesis. CONCLUSIONS: We report a female with a phenotype compatible with aromatase deficiency which was unrecognised until adulthood and found she had a novel duplication in CYP19A1. Previous case reports have described polycystic ovarian morphology, especially in childhood and adolescence, but never streak ovaries. This may reflect the few adult cases reported, that aromatase deficiency in females is generally diagnosed at birth and oestrogen treatment commences decades earlier than occurred in our patient. Streak ovaries are consistent with the phenotype of the aromatase knockout mouse followed through adulthood. The observed clinical features of obesity, dysglycaemia and hypertension, are compatible with the observation that lack of a counterbalancing effect of oestrogen on tissue androgens until adulthood may lead to a metabolic syndrome phenotype. This report broadens the spectra of phenotype and genetic mutations underlying this rare disorder.

Dataset Information

The Association of CYP19A1 Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can CYP19A1 Variants Be Used to Predict Treatment Efficacy?

Publications

The Association of <i>CYP19A1</i> Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can <i>CYP19A1</i> Variants Be Used to Predict Treatment Efficacy?

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