Naslov
POVEZANOST SKLEROSTINA I DICKKOPFA 1 TE FUNKCIONALNIH GENSKIH POLIMORFIZAMA INHIBITORA AROMATAZE S INDIVIDUALNIM RAZLIKAMA U UČESTALOSTI I TEŽINI NEŽELJENIH POPRATNIH POJAVA LIJEČENJA
(Association of sclerostin, dickkopf 1 and functional genetic aromatase inhibitors polymorphisms with interpatient variability in the frequency and intensity of adverse effects)

Autori
Bojanić, Kristina

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, doktorska disertacija

Fakultet
Medicinski fakultet Osijek

Mjesto
Osijek

Datum
10.12

Godina
2018

Stranica
94

Mentor
Smolić, Martina

Ključne riječi
dickkopf 1 protein, ljudski ; farmakogenomika ; inhibitor aromataze ; osteoporoza ; SOST protein, ljudski
(aromatase inhibitor ; dickkopf 1 protein, human ; pharmacogenomics ; osteoporosis ; SOST protein, human)

Sažetak
Anastrozole is the first choice treatment in postmenopausal women with hormone-dependent breast cancer (HR-BC). Cytokine P450 (CYP) and UDP-Glucuronosyltransferase (UGT) have a key role in deactivating and eliminating anastrozole. The negative effect of anastrozole on bone metabolism has been demonstrated, while the effect on Wnt inhibitors is still being investigated. The aim of the study was to determine the circulating levels of Wnt inhibitors in HR-BC patients treated with anastrozole and compare them with patients with breast cancer prior to the introduction of the adjuvant hormonal therapy. We also investigated the association of Wnt inhibitors with bone mineral density (BMD) and dietary and life habits of participants. Single nucleotide polymorphisms (SNPs) in genes encoding CYP and UGT may play a key role in individual responses to anastrozole. The aim was to determine the frequency of mutated CYP3A4*1B, CYP3A5*3 and UGT1A4*2 alleles and to investigate their correlation with the outcome of adjuvant hormonal treatment and the occurrence of side effects. Participants and methods: Cross- sectional study included 141 postmenopausal HR- BC patients, of whom 85 were treated with 1 mg of anastrozole, and 56 were included prior to the introduction adjuvant hormonal therapy. Serum concentrations of Wnt inhibitors were measured using commercially available ELISA assays. BMD ; g/cm2 was measured by dual-energy x-ray absorptiometry (DXA) imaging (Lunar Prodigy, GE Healthcare, SAD) and a self- reported questionnaire was used to investigate the lifestyle and eating habits of the examinees. Genomic DNA was isolated from peripheral blood samples using commercially available kit (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Germany). A real-time PCR was used for the detection of polymorphisms, with the application of the specific TaqMan® SNP Genotyping Assay (Applied Biosystems). Results: Serum levels of sclerostin were significantly higher in the group of participants treated with anastrozole (31.8 pmol/l) compared to the w/o anastrozole therapy group (24.1 pmol/l, p<0.001). In contrast, the serum DKK1 level was significantly lower in the anastrozole treated group (24.3 pmol/l at 26.02 pmol/l, p <0.001). Total hip and femoral neck BMD were significantly lower in the group treated with anastrozole. Statistically significant negative correlation between sclerostin and DKK1 (rho=-0.287, p<0.001) was observed in all participants. CYP3A5*3 was found to be predominant in the Craotian population of HR-BC patients. We have demonstrated a strong linkage disequilibrium between CYP3A5*3 and CYP3A4*1B alleles in the same group of participants. Conclusion: Increased serum levels of sclerostin and decreased levels of DKK1 are associated with the anastrozole treatment. The correlation of the investigated polymorphisms with the onset of treatment side effects has not been established.

Izvorni jezik
Hrvatski

POVEZANOST RADA