Zafer Cetin

Effects of hormone replacement therapy on bone mineral density in Turkish patients with or without COL1A1 Sp1 binding site polymorphism

Aim:  To evaluate the effects of hormone replacement therapy (HRT) on bone mineral density (BMD) in patients with or without COL1A1 Sp1 binding site polymorphism.

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR

Signaling pathways activated by epidermal growth factor receptors (EGFRs) are important in lung carcinogenesis. New treatment strategies with EGFR-targeting drugs provided improvements in management of lung cancer. However, molecular mechanisms underlying resistance to these drugs need to be evaluated. Surgically resected samples were obtained from 50 patients with non-small-cell-lung cancer. PTEN, Mcl-1 and EGFR protein expression levels were evaluated by Western-blot. Direct sequencing was performed to investigate EGFR tyrosine kinase domain mutations. We detected c.2235-2249 (pGlu746-Ala750del) mutation in exon 19 in two patients with adenocarcinoma histology. Elevated expression levels of both Mcl-1 isoforms (Mcl-1S and Mcl-1XL) and EGFR proteins were found in 15 (30%) and 23 (46%) of the cases, respectively. Reduced PTEN protein expression levels were observed in 17 (34%) of the cases. PTEN expression level was reduced in 26% of cases that showed increased EGFR expression. Also, increased expression of Mcl-1 protein was observed in 26% of cases with EGFR overexpression. One of the cases harboring pGlu746-Ala750del mutation had increased levels of Mcl-1 and decreased PTEN expression levels. Our results indicate that, in addition to lack of PTEN expression, elevated levels of the Mcl-1 protein might be one of the important intrinsic mechanisms protecting non-small–cell-lung cancer cells from apoptosis induced by several compounds. Therefore, EGFR mutations in conjunction with evaluation of Mcl-1 and PTEN expression levels in large cohorts might provide important clues for improvements of new treatment strategies in non-small–cell-lung cancer management.

Relationship between SP1 polymorphism and osteoporosis in β-thalassemia major patients

Background: β‐Thalassemia is an autosomal recessive disease characterized by defective β‐globin chain production. Osteoporosis is an important cause of morbidity in patients with β‐thalassemia major. The pathogenesis of reduced bone mineral density (BMD) is multifactorial. A range of genetics factors have been implicated in other populations of patients with osteoporosis. Polymorphism at the Sp1 binding site of the collagen type I A1 (COLIA1) gene is thought to be an important factor in the development of osteoporosis.

Pure and complete 12p trisomy due to a maternal centric fission of chromosome 12

Pure and complete 12p trisomy are rare. Here, we report on a unique patient with trisomy 12p syndrome due to centric fission of maternal chromosome 12. Conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques revealed the propositas karyotype to be 47,XX,+fis(12)(p10)mat whereas the maternal one was 47,XX,‐12,+fis(12)(p10),+fis(12) (q10). This is the first report on centric fission of chromosome 12 leading to stable telocentrics, each with a fully functional centromere. Our observation shows that the centric fission of chromosome 12 can be a new mechanism for generation of a partial centromere and trisomy 12p syndrome.

A 5q12.1–5q12.3 microdeletion in a case with a balanced exceptional complex chromosomal rearrangement

Complex chromosomal rearrangements are very rare chromosomal abnormalities. Individuals with a complex chromosomal rearrangement can be phenotypically normal or display a clinical abnormality. It is believed that these abnormalities are due to either microdeletions or microduplications at the translocation breakpoints or as a result of disruption of the genes located in the breakpoints. In this study we describe a 2-year-old child with mental retardation and developmental delay in whom a de novo apparently balanced exceptional complex chromosomal rearrangement was found through conventional cytogenetic analysis. Using both cytogenetic and FISH analysis, the patients karyotype was found to be: 46,XY,der(5)t(5;7)(p15.1;7q34),t(5;8)(q13.1;8q24.1)dn. A large, clinically significant deletion which encompassed 887.69kb was detected at the 5q12.1-5q12.3 (chr5:62.886.523-63.774.210) genomic region using array-CGH. This deleted region includes the HTR1A and RNF180 genes. This is the first report of an individual with an apparently balanced complex chromosomal rearrangement in conjunction with a microdeletion at 5q12.1-5q12.3 in which there are both mental-motor retardation and dysmorphia.

A patient with Down syndrome with a de novo derivative chromosome 21

Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions.

Evaluation of eNOS gene polymorphisms in relation to BMD in postmenopausal women

OBJECTIVE The aim of the present study was to evaluate the relations between T(-786)C and Glu298Asp polymorphisms of the endothelial nitric oxide synthase (eNOS) gene and BMD in postmenopausal Turkish women. METHODS The T(-786)C and Glu298Asp polymorphisms were genotyped by PCR-RFLP method in 311 postmenopausal osteoporotic women (OP) and in 305 age-matched postmenopausal females (CG) with normal BMD. RESULTS None of the SNPs of the eNOS gene was significantly associated with BMD at the lumbar spine, femoral neck, Wards triangle and femoral trochanter in the combined group. Mean BMD values were therefore found to be similar across the genotypes in postmenopausal Turkish women. However, there was a significant association between the T(-786)C polymorphism and BMD values at the lumbar spine in the normal control group (P=0.005), and at the femoral trochanter in the osteoporotic patients (P=0.046). The mean value of the lumbar spine BMD in the normal controls was significantly higher in women with the TC genotype of the T(-786)C polymorphism than in women with the TT genotype (P=0.0012). Women with the CC genotype of the T(-786)C polymorphism in the osteoporotic patients had significantly higher BMD value at the femoral trochanter than those with the TC (P=0.018) and TT genotypes (P=0.024). Frequencies of the TC heterozygotes for T(-786)C polymorphism were significantly higher among osteoporotic subjects than normal controls. Also, the CC and TT genotype frequencies of control group were significantly higher than those of the osteoporotic group at the femoral neck. CONCLUSIONS We conclude that, although the biological role of the nitric oxide synthases is well established, our study does not suggest that eNOS gene polymorphisms, T(-786)C and Glu298Asp, are major contributors to adult bone mineral density in the postmenopausal Turkish women.

Exceptional complex chromosomal rearrangement and microdeletions at the 4q22.3q23 and 14q31.1q31.3 regions in a patient with azoospermia

In this report we describe the first patient ever found to have azoospermia in association with both exceptional complex chromosomal rearrangements and microdeletions at two translocation breakpoints. A 36-year-old male who had been suffering from male factor infertility was admitted to our clinic. The patient also displayed mild dysmorphia. An analysis of the patients semen revealed azoospermia. GTG banding revealed the presence of an exceptional complex chromosomal rearrangement involving chromosomes 1, 4, 10 and 14. Using subtelomeric FISH analysis, the patients karyotype was designated as 46,XY,t(1;10)(q43q44;q21q26.1)(CEB108/T7+,D1S3738-;10PTEL006+,D10S2290+, D1S3738+), ins(14;4) (q31.3;q23q33)(D14S1420+; D4S3359+, D4S2930+). Array-CGH analysis revealed two microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions. We suggest that microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions associated with both an exceptional complex chromosomal rearrangement and the Homo sapiens chromosome 4 open reading frame 37 (C4orf37) gene located at the 4q22.3q23 region might be associated with male factor infertility.

Chromosome abnormalities identified in 457 spontaneous abortions and their histopathological findings.

Abstract Objective: About 15% of clinically recognized pregnancies result in spontaneous abortion in the first trimester and the vast majority of these are the result of chromosome abnormalities. Studies of chromosomal constitutions of first trimester spontaneous abortions have revealed that at least 50% of the abortions have an abnormal karyotype. In this study we aimed to report the single centre experience of anomalies detected in spontaneous abortions. Material and Method: We present rare numerical and structural cytogenetic abnormalities detected in spontaneous abortion materials and the histopathological findings of rest material of abortion specimens in our study population. Results: Among 457 cases, 382 were successfully karyotyped while cell culture of 75 cases failed. Cytogenetic abnormalities were detected in 127 of 382 cases (33.24%). Autosomal trisomies were the predominant chromosomal abnormalities with a frequency of 48.8%. Structural chromosomal abnormalities were infrequent in conception materials. The mean age of the mothers was highest in trisomy group, the difference being significantly important (ANOVA p< 0.001). The most frequent chromosomal abnormalities were Turner syndrome, triploidy and trisomy of chromosome 16 followed by trisomy of chromosomes 22 and 21 and tetraploidy. Double trisomies and structural chromosomal abnormalities were rare. Trisomies were more frequent in advanced maternal age. Conclusion: Detection of chromosomal abnormalities in spontaneous abortion materials is very important to clarify the causes of loss of pregnancy. Detection of structural chromosomal abnormalities in the cases and their carrier parents can provide proper genetic counseling to these families. These families can be directed towards pre-implantation genetic diagnosis to prevent further pregnancies with complications. Öz Amaç: Klinik olarak gebeliklerin yaklaşık %15’i ilk trimesterde abortus ile sonuçlanmakta olup büyük kısmında ise neden kromozom anormallikleridir. Çalışmalar göstermiştir ki ilk trimesterda abortusla sonuçlanan gebeliklerin %50’sinde kromozomal olarak karyotip anomalileri görülmüştür. Çalışmada tek merkeze ait spontan abortus olgularındaki anomalileri sunmak amaçlandı. Gereç ve Yöntem: Çalışmada tıbbi biyoloji ve genetik bölümümüze gelen spontan abortus materyallerinde tespit edilen sayısal ve yapısal sitogenetik anomalileri ve bu olguların histopatolojik bulguları sunuldu. Bulgular: Karyotipleme için gelen 457 spontan abortus materyalinin 382 tanesinde başarılı karyotipleme yapılabilmiştir, 75 olguda hücre kültürü başarısız olmuştur. Sitogenetik anomaliler 382 olgunun 127’sinde görülmüştür (%33.24). Otozomal trizomiler %48,8 oranı ile en baskın görülen anomalidir. Yapısal anomaliler abortus materyallerinde pek sık değildir. Ortalama anne yaşının en yüksek olduğu anomali grubu trizomi grubudur ve fark istatistiksel olarak anlamlıdır (ANOVA p< 0.001). En sık görülen kromozomal anomaliler Turner sendromu, triploidi ve trizomi 16’dır. Bunları trizomi 22, 21 ve tetraploidi takip eder. Çalışmada çift trizomiler ve yapısal kromozom anomaliler nadirdir. Anne yaşı ileri olursa trizomiler daha sık görülmektedir. Sonuç: Sonuç olarak spontan abortus materyallerinde kromozom anomalilerinin değerlendirilmesi gebelik kayıplarının sebeplerini açığa çıkarmak için önemlidir. Yapısal kromozom anomalilerinin tespit edilmesi aileye sonraki gebeliklerde daha iyi genetik danışmanlık verilmesine yardımcı olur. Bu ailelere bir sonraki gebeliklerinde komplikasyonları önlemek için preimplantasyon döneminde genetik tanı ile rehberlik edilebilir.

Rare Structural Chromosomal Abnormalities in Prenatal Diagnosis; Clinical and Cytogenetic Findings on 10125 Prenatal Cases / Prenatal Tanıda Nadir Yapısal Kromozom Anomaliler; 10125 Prenatal Olgunun Klinik ve Sitogenetik Bulguları

ABSTRACT Objective: The aim of this study was presentation of the ultrasonographic findings and perinatal autopsy of cases with rare chromosomal abnormalities. Material and Method: A total of 10125 prenatal cases over 17 years including 8731 amniocentesis, 973 chorionic villus sampling, and 421 fetal blood sampling cases were evaluated for prenatal cytogenetic diagnosis. Conventional cytogenetic studies, fluorescence in situ hybridization studies, and Array-CGH analysis techniques were used for genetic analysis. Results: A structural chromosomal abnormality was observed in 95 cases. The most frequently observed structural abnormalities were balanced translocations with a frequency of 53.7% (51 cases) followed by unbalanced translocations (16.8%), inversions (11.6%), supernumerary marker chromosomes (8.4%), duplications (4.2%), deletions and ring chromosomes (2.1%) and complex translocation (1.1%). Rare structural chromosomal abnormalities including de novo balanced translocations, unbalanced translocations, inversions, duplications, deletions, ring chromosomes, and supernumerary marker chromosomes were detected in 24 cases. Conclusion: The rate of rare chromosomal abnormalities varies from 2.4% (South East Ireland) to 12.9% (Northern England) in Europe with a total rate of 7.4/10 000 births. In our study, the overall rate of chromosomal abnormality in prenatal cytogenetic diagnosis was 3.7%, similar to South East Ireland. Ultrasonographic and perinatal autopsy findings of the cases with rare structural chromosomal abnormalities are important for proper genetic counseling for further similar cases. ÖZ Amaç: Çalışmada nadir kromozomal anomalilerin ultrasonografik ve perinatal otopsi bulgularını sunmayı amaçladık. Gereç ve Yöntem: Çalışmada 17 yıllık bir süreçte hastanemize prenatal sitogenetik değerlendirmeye gelen 10125 olguyu ele aldık. Olguların 8371’i amniyosentez, 973’ü koryonik villus örneklemesi ve 421’i fetal kan örneğinden oluşmaktadır. Genetik analiz için konvasiyonel sitogenetik yöntemler, floresan in situ hibridizasyon ve array-CGH teknikleri kullanılmıştır. Bulgular: Yapısal kromozomal anomaliler 95 olguda görüldü. En sık görülen yapısal anomali grubunu %53,7 oranı (51 olgu) ile dengeli translokasyonlar oluşturmakta olup, bunu %16,8 ile dengesiz translokasyonlar, %11,6 ile inversiyonlar, %8,4 ile ilave marker kromozomlar, %4,2 ile duplikasyonlar, %2,1 ile delesyon ve ring kromozomlar, %1,1 ile kompleks translokasyonlar izlemektedir. De novo dengeli translokasyonlar, dengesiz translokasyonlar, inversiyonlar, duplikasyonlar, delesyonlar, ring kromozomlar ve ilave marker kromozomlardan oluşan nadir yapısal anomaliler 24 olguda tespit edilmiştir. Sonuç: Nadir kromozomal anomalilerin oranları Avrupa’da %2,9 (Güney Doğu İrlanda) ile %12,9 (Kuzey İngiltere) arasında değişmektedir ve toplamda oran 7,4 / 10 000 doğumdur. Çalışmada prenatal sitogenetik tanıda genel kromozomal anomali oranı %37 olup, Güney Doğu İrlanda’ya benzerdir. Nadir yapısal kromozom anomalilerine sahip olguların prenatal ultrasonografik değerlendirmeleri ve perinatal otopsi sonuçları diğer benzer olgulara doğru genetik danışma vermek için oldukça önemlidir.