Faculty of Medicine

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CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer
(Walter de Gruyter GmbH, 2012-06)
Madjunkova, S
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Georgiev, V
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Petrovski, D
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Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ± 2.65, in controls 22.28 ± 2.86 (p = 0.009) and in BPH patients 22.1 ± 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.
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Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia
(Walter de Gruyter GmbH, 2014-12)
Kapedanovska Nestorovska, A
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Naumovska, Z
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Hiljadnikova Bajro, M
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Sterjev, Z
Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry.
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T-lymphoblastic leukemia/lymphoma in macedonian patients with Nijmegen breakage syndrome
(Walter de Gruyter GmbH, 2016-07-01)
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Antevska-Trajkova, Z
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Coneska-Jovanova, B
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Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to malignancy. The gene responsible for the disease, NBS1, is located on chromosome 8q21 and encodes a protein called nibrin. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS. In this report, we describe two patients with NBS and T-lymphoblastic leukemia/lymphoma in a Macedonian family. To the best of our knowledge, this is the first family with NBS reported from Macedonia. Both children presented with microcephaly, syndactyly and the development of T cell lymphoblastic lekemia/lymphoma at the age of 7 and 10 years, respectively. The molecular analysis of NBS1 genes in our patients showed homozygosity for the 657del5 mutation in the NBS1 gene. The parents were heterozygotes for the 657del5 mutation and they had no knowledge of a consanguineous relationship. The first child was treated with the International Berlin-Frankfurt-Münster (BFM)-Non Hodgkin lymphoma (NHL) protocol and achieved a complete remission that lasted for 21 months. Subsequently, he developed a medullar relapse with hyperleukocytosis and died due to lethal central nervous system (CNS) complications. The second child was treated according to the International Collaborative Treatment Protocol for Children and Adolescents with Acute Lymphoblastic Leukemia 2009 (AIOP-BFM ALL 2009) protocol. Unfortunately, remission was not achieved.
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BRAFV600E mutational status in thyroid carcinoma patients - single center study
(Springer Science and Business Media LLC, 2021)
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Jankulovska, A
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Stoilovska, B
Aim/Introduction: Thyroid carcinomas (TCs) are one of the most genetically evaluated carcinomas. The BRAFV600E mutation is the most frequent genetic alteration, but it isn`t still routinely recommended in the initial evaluation of the TCs patients. The aim of our study was to evaluate BRAF mutational status in TCs patients and to correlate it with clinical features: initial stage, age at diagnosis and post ablative 131 I scan in relation to presence or absence of BRAFV600E mutation. Materials and Methods: Fifty-two patients with TCs were evaluated for BRAFV600E mutational status from the primary tumor tissue. Retrospective analysis of the medical data and postoperative histopathology reports were performed to determine the histopathological type of tumor and the initial stage. Three nuclear medicine physicians with more than 10 years’ experience reviewed the post ablative radioiodine whole body scans (WBS). Patients were followed for average 4 years (SD ± 2.7years). Results: We found that 32 out of 52 TCs patients or 63.46% were BRAFV600E + mutation and all of them were papillary thyroid carcinomas (PTC), or 21 typical variants, 9 follicular variants and one patient each were: Warthin like, tall cell and Hurthle cell variants of PTC. BRAFV600E - were 19 (36.54%) patients (4 being follicular thyroid carcinomas and 15 patients PTC). The average age at the moment of diagnosis was similar in both groups, or 45 years ±15.25 in BRAFV600E - group and 48 ± 13.26 years in BRAFV600E + group. Regarding the initial stage in BRAFV600E - group, 55% were TNM stage I, 25% stage II, 10% stage III and 10% Stage IV and BRAFV600E + group were 53.125% Stage I, 21.875% Stage II, 21.875% Stage III and 3.125% Stage IVa. Post ablative WBS scan detected remnant thyroid tissue accumulation in all BRAFV600E + patients. In four BRAFV600E - patients the scan revealed distant metastases in 3 patients, while accumulation in neck lymph nodes in 1 patient. Conclusion: Analysis hasn’t revealed significant difference in age at diagnosis, initial staging and post ablative 131 I WBS scans among BRAFV600E + and - groups. Longer follow-up is recommended to discover the true meaning of BRAFV600E in the prognostication.
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Programmed death-ligand 1 expression in triple negative breast cancer
(Springer, 2019-09)
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Background & Objectives: Triple negative breast cancer (TNBC) account for 10-20% of all breast subtypes and are associated with poor prognosis. There is no approved targeted therapy for these patients, yet. Programmed death-ligand 1 (PD-L1) expression has been identified in different cancers achieving good results with immunotherapy. There is limited data reporting the PD-L1 expression in TNBC. The aim of this study is to evaluate the expression of PD‑L1 in TNBC patients and to analyse the relationship between PD‑L1 expression and clinicopathological features of the patients. Methods: Paraffin tissue blocks from 19 TNBC patients were used. PD-L1 immunohistochemistry was performed using monoclonal mouse anti-PD-L1, Clone 22C3. Expression of PD-L1 was correlated with clinicopathological features. Tumours were defined as PD-L1 positive if there was membranous expression in ≥ 1% of tumour cells. Results: Median age at diagnosis was 56 (range 33-74). PD-L1 was expressed in 7 (36, 8%) of the patients. Six of the patients showed low PD-L1 expression (3-20%) and only one patient showed high expression (>50%). The PD-L1 expression showed no significant correlation with clinicopathological parameters. Although statistically not significant (p>0,05), PD-L1 was more often expressed in high grade tumours with larger size, high clinical stage and mutated p53. Conclusion: Expression of PD-L1 was found in more than one third of TNBC and correlated with poor prognostic factors. PD‑L1 may be a significant marker for predicting prognosis of TNBC patients. These data need to be confirmed in larger study group.
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Effects of single nucleotide polymorphisms and haplotypes of the SLCO1B1 gene on the pharmacokinetic profile of atorvastatin in healthy Macedonian volunteers
(Govi-Verlag (Germany)/Ingenta Connect, 2015-07)
Daka, A
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Eftimov, A
OATP1B1 is an influx transporter known to mediate the uptake of various endogenous compounds and xenobiotics. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1. The aim of this study was to investigate the effects of SLCO1B1 polymorphisms on the pharmacokinetics of atorvastatin in healthy volunteers of Macedonian origin. Twenty three participants, genotyped for SLCO1B1 c.388A > G, c.521T > C, c.571T > C, c.597C > T, c.1086C > T, c.1463G > C and c.*439T > G polymorphisms using TaqMan allelic discrimination assay, ingested a single 80 mg dose of atorvastatin. The plasma concentrations of atorvastatin were measured for 48 h using Tandem Liquid Chromatography-Mass Spectrometry, LC-MS-MS, and the peak plasma concentration (C(max)), time to peak plasma concentration (T(max)), elimination half-life (t1/2), constant rate of elimination (k(el)), mean residence time (MRT, expo), volume of distribution (Vd/kg), clearance (CL/kg), area under curve AUC(0.48h) and AUC(0-∞), were determined. Our data confirmed that the SLCO1B1 gene is highly polymorphic, with a frequency of the c.521T > C single-nucleotide polymorphism (SNP) being the lowest (app. 15%) and of all other SNPs alleles above 40%. Exceptions were c.1463G > C and c.1086C > T SNPs for which variant alleles were not identified. The strongest correlation was observed between the c.521T > C and c.571T > C SNPs pair. The haplotype analysis revealed 10 different haplotypes, with *1J/*1K/*1L being the dominant, with a frequency of app. 40%. The haplotype *15/*16/*17, containing both variant alleles of the functionally most distinguished SNPs, c.388A > G and c.521T > C, occurred with a frequency of 13%. However, *15/*16/*17 homozygotes were not identified in the study group. In this study, no significant differences in the k(el), t1/2, C(max), T(max), AUC(0-48h), AUC(0-∞), MRT expo, Vd and CL between the carriers of different c.388A > G, c.597C > T and c.*439T > G genotypes were observed. Subject with a variant allele C in the c.521T > C SNP, c.521CC genotype, had markedly higher values for C(max) and AUC(0.48h), 140% and 67%, respectively, in comparison with the carriers of the c.521TT genotype. Also, the carriers of the variant allele C at c.571T > C SNP, c.571 CC genotype, had 55% and 43% lower mean C(max) and AUC(0-48h) in comparison with the carrier of c.571TT. These differences lacked statistical significance due to the size of the sample. In addition, no significant differences in the pharmacokinetic parameters of atorvastatin between the *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers were observed. In conclusion, this extensive analysis of the effect of SLCO1B1 polymorphisms on the pharmacokinetic profile of atorvastatin showed that c.521T > C and c.571T > C SNPs may affect the inter-individual response to atorvastatin. Additional studies, with a large sample size, are needed to confirm this finding.
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Rhabdomyolysis and Cardiomyopathy in a 20-Year-Old Patient with CPT II Deficiency
(Hindawi Limited, 2014-01-20)
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Zafirovska, P
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Caparovska, E
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Pocesta, B
Aim. To raise the awareness of adult-onset carnitite palmitoyltransferase II deficiency (CPT II) by describing clinical, biochemical, and genetic features of the disease occurring in early adulthood. Method. Review of the case characteristics and literature review. Results. We report on a 20-year-old man presenting with dyspnea, fatigue, fever, and myoglobinuria. This was the second episode with such symptoms (the previous one being three years earlier). The symptoms occurred after intense physical work, followed by a viral infection resulting in fever treated with NSAIDs. Massive rhabdomyolysis was diagnosed, resulting in acute renal failure necessitating plasmapheresis and hemodialysis, acute hepatic lesion, and respiratory insufficiency. Additionally, our patient had cardiomyopathy with volume overload. After a detailed workup, CPT II deficiency was suspected. We did a sequencing analysis for exons 1, 3, and 4 of the CPT II gene and found that the patient was homozygote for Ser 113 Leu mutation in exon 3 of the CPT II gene. The patient recovery was complete except for the cardiomiopathy with mildly impaired systolic function. Conclusion. Whenever a patient suffers recurrent episodes of myalgia, followed by myoglobinuria due to rhabdomyolysis, we should always consider the possibility of this rare condition. The definitive diagnose of this condition is achieved by genetic testing.
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Correlation of mRNA-TSHR expression with clinical parameters in thyroid carcinoma patients
(Nature Publishing Group, 2019-10-10)
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Jovanovic, H

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