Browsing by Author "Özen, Ahmet"

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The evaluation of malignancies in Turkish primary immunodeficiency patients; A multicenter study
(Wiley, 2020-02-14) Metin, Ayşe; Aytekin, Caner; Karaca, Neslihan Edeer; Barış, Safa; Kıykım, Ayça; Aydıner, Elif Karakoç; Özen, Ahmet; Aksu, Güzide; Kütükçüler, Necil; Çekiç, Şükrü; Karalı, Yasin; Aslan, Törehan; Sevinir, Betül; Kılıç, Sara Şebnem; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları.; 0000-0002-9574-1842; 0000-0002-3966-4635; 0000-0003-4150-5200; FFS-1974-2022; AAH-1570-2021; 56117061000; 57188056500; 49863694000; 6603199915; 34975059200
Background There are no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. Method Between the years 1992 and 2018, from five tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. Results The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male-to-female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5-51). The median age at diagnosis of malignancy was 10 years (range: 1.5-51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n = 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n = 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n = 7/43, 16.3%) was higher than AT (n = 19/193, 9.8%), Wiskott-Aldrich syndrome (n = 2/22, 9.1%), and common variable immunodeficiency (n = 11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. Conclusion This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency compared to AT.
Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations
(Oxford Univ Press, 2022-05-02) Çekiç, Şükrü; Hüriyet, Hüzeyfe; Hortoğlu, Melika; Kasap, Nurhan; Özen, Ahmet; Karakoç-Aydıner, Elif; Metin, Ayşe; Ocakoğlu, Gökhan; Demiröz Abakay, Candan; Temel, Şehime G.; Özemri Sağ, Şebnem; Barış, Safa; Çavaş, Tolga; Şebnem Kılıç, Sara; ÇEKİÇ, ŞÜKRÜ; Hüriyet, Hüzeyfe; BEKTAŞ HORTOĞLU, MELİKA; OCAKOĞLU, GÖKHAN; DEMİRÖZ ABAKAY, CANDAN; TEMEL, ŞEHİME GÜLSÜN; ÖZEMRİ SAĞ, ŞEBNEM; ÇAVAŞ, TOLGA; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Pediatrik İmmünoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü/Hücre Kültürü ve Genetik Toksikoloji Laboratuvarı.; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Biyoistatistik Anabilim Dalı.; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Radyasyon Onkolojisi Anabilim Dalı.; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Translasyonel Tıp Anabilim Dalı.; 0000-0002-9574-1842 ; 0000-0002-5617-8313 ; 0000-0001-5380-5898 ; 0000-0003-1620-1918 ; L-1933-2017; CVI-9578-2022; JBJ-7521-2023; HLG-6346-2023; AAH-3855-2021; AAG-8385-2021; AAH-8355-2021; AAH-3508-2021; IMT-6140-2023
STAT3 plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis. The transcriptional activity of the STAT3 gene is controlled by a transcription factor called ZNF341. There is insufficient data on radiation sensitivity and post-radiation DNA repair in STAT3- loss-of-function (LOF) patients. We aimed to investigate the radiosensitivity in patients with STAT3-LOF and ZNF341 deficiency. Twelve patients with STAT3-LOF and four ZNF341-deficiency patients were recruited from three clinical immunology centers in Turkey and evaluated for radiosensitivity by the Comet assay, comparing to 14 age- and sex-matched healthy controls. The tail length (TL) (mu m), percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2 Gy irradiation), and recovery (2 h after irradiation) periods by using a computerized image-analysis system, estimating DNA damage. Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups. During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms. Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation.This study demonstrates for the first time that patients with STAT3-LOF and ZNF341 deficiency had increased radiation sensitivity and DNA repair defects compared with healthy controls. Our results highlight the need for close monitoring of these patients for the development of malignancy.
Mutational landscape of severe combined immunodeficiency patients from Turkey
(Wiley, 2020-06-02) Fırtına, Sinem; Ng, Yuk Yin; Ng, Özden Hatırnaz; Kıykım, Ayça; Aydiner, Elif; Nepesov, Serdar; Camcıoğlu, Yıldız; Sayar, Esra H.; Reisli, Ismail; Torun, Selda H.; Çöğürlü, Tuba; Uygun, Dilara; Şimşek, Işıl E.; Kaya, Ayşenur; Çipe, Funda; Çağdaş, Deniz; Yücel, Esra; Uygun, Vedat; Barış, Safa; Özen, Ahmet; Özbek, Uğur; Sayitoğlu, Müge; Çekiç, Şükrü; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk İmmünoloji Anabilim Dalı.; 0000-0002-9574-1842; L-1933-2017; 56117061000
Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.
Primary antibody deficiencies in Turkey: Molecular and clinical aspects
(Humana Press, 2021-09-30) Fırtına, Sinem; Ng, Yuk Yin; Ng, Özden H.; Kıykım, Ayça; Özek, Esra Yücel; Kara, Manolya; Aydıner, Elif; Nepesov, Serdar; Camcıoğlu, Yıldız; Sayar, Esra H.; Güngören, Ezgi Yalçın; Reisli, İsmail; Torun, Selda H.; Haskoloğlu, Şüle; Çoğurlu, Tuba; Kaya, Ayşenur; Çekiç, Şükrü; Barış, Safa; Özbek, Uğur; Özen, Ahmet; Sayitoğlu, Müge; ÇEKİÇ, ŞÜKRÜ; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Pediatrik İmmünoloji Anabilim Dalı.; 0000-0002-9574-1842; L-1933-2017
Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.
The evaluation of radiosensitivity in patients with STAT3 deficiency
(Springer, 2021-04-01) Çekiç, Şükrü; Hüriyet, Hüzeyfe; Hortoğlu, Melika; Barış, Safa; Metin, Ayşe; Özen, Ahmet; Aydıner, Elif Karakoç; Abakay, Candan; Çavaş, Tolga; Kılıç, Sara; ÇEKİÇ, ŞÜKRÜ; Hüriyet, Hüzeyfe; BEKTAŞ HORTOĞLU, MELİKA; DEMİRÖZ ABAKAY, CANDAN; ÇAVAŞ, TOLGA; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk İmmunoloji Bilim Dalı.; 0000-0002-9574-1842; 0000-0001-8494-601X; 0000-0003-4150-5200; AAA-4154-2022; JBJ-7521-2023; R-6749-2017; L-1933-2017; HKN-1599-2023