تقييم تاثير تعدد الاشكال الجيني لجين SULT1A1على الاستجابة العلاجية لعقار التاموكسفين في عينة من مرضى سرطان الثدي

Evaluation of the Effect of Genetic Polymorphism of SULT1A1 on Therapeutic Response of Tamoxifen in a Sample of Breast Cancer Patients

Abstract
Background Breast cancer is the most frequent malignancy diagnosed in females around the world.
Tamoxifen is the hormonal drug used as selective estrogen receptor modulator in the treatment of hormone receptor positive breast cancer in premenopausal women with early or metastatic stage. Being a prodrug, tamoxifen undergo metabolism by phase I and phase II enzymes into primary and secondary metabolites that show its therapeutic effect. Genetic polymorphism of sulfotransferase SULT1A1, one of the phase II drug metabolizing enzymes may affect clinical response to the drug.

Aims of study: The aim of the present study was to identify the genetic polymorphism of SULT1A1 gene (rs 6839 and rs 9282861) in the participated breast cancer women, and to investigate the impact of SULT1A1 genetic polymorphism on tamoxifen efficacy.

Patients and methods This is an observational cross-sectional study conducted at Imam Al-Hussein Medical City/Oncology Center in Kerbala. One hundred female patients with breast cancer that was estrogen-receptor and / or progesterone-receptor positive were selected. Patients aged 45-65 years, being on tamoxifen 20mg daily dose for at least 3 months had enrolled in this study. Venous blood samples were drawn from each female after they are signed written informed consent to measure biochemical parameters such as estradiol, CA15-3, vitamin D, calcium, and lipid profile in addition to genetic analysis. The Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS PCR) was used for the detection of SULT1A1 gene rs 6839 and rs 9282861.

Results: The results of this study revealed that there were various genetic variants of SULT1A1 gene included rs 6839 (902T>C) and rs 9282861(638C>T). In case of rs 6839, the homozygous wild (TT) is the predominant genotype compared to homozygous mutant (CC) and the heterozygous mutant (TC) genotypes with frequency of 54, 29 and 17 respectively. However, for rs 9282861, the homozygous mutant (TT) is the predominant genotype in comparison to the heterozygous mutant (CT) and homozygous wild (CC) genotypes with frequency of 41, 21 and 38 respectively. The levels of estradiol, tumor marker CA15-3, calcium, vitamin D3, cholesterol, triglycerides, HDL and LDL in the serum showed non-significant association between the studied SNPs of SULT1A1 gene. Moreover, the current study demonstrated that there is high occurrence of joint pain over 76% with low recurrence rate about 7%.

Conclusion
The current investigation concluded that genetic variation in phase II metabolizing enzyme SULT1A1 may be contributed to variability in response to tamoxifen therapy in a sample of breast cancer Iraqi women beside variation in the incidence of adverse drug reactions.