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    A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings
    (Elsevier Masson s.r.l., 2024) Khodzhaev, Khusan; Sudutan, Tuğce; Erbilgin, Yücel; Sarıtaş, Merve; Yeğen, Gülçin; Bozkurt, Ceyhun; Sayitoğlu, Müge; Kebudi, Rejin
    Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL. The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G>A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased PXR expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells. Patients with homozygous PXR variant showed significantly high expression compared to PXR wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). PXR homozygous HRS cells had significantly higher PXR expression compared to PXR wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous PXR HRS cells showed increased PXR expression in nucleus (p < 0.001). PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous PXR HL cases. This study provided clinical evidence to previously reported Sxr−/− mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis. © The Authors
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    Activation-Induced cytidine deaminase (AID) and uracil N-glycosylase (UNG) novel homozygous gene variants in adult hyper-IgM syndrome
    (2021) Yılmaz, Hülya; Fırtına, Sinem; Sarıtaş, Merve; Ar, Muhlis Cem; Sayitoğlu, Müge
    Activation-Induced Cytidine Deaminase (AID) and Uracil N-glycosylase (UNG) novel homozygous gene variants in adult hyper-IgM syndrome
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    Dasatinib-related pleural effusion and lymphocytosis rates are different between adult and pediatric patients with Philadelphia chromosome-positive leukemias: are age and comorbidities only to blame?
    (Taylor and Francis, 2022) Kılıçarslan, Necati Alp; Börekçi, Şermin; Özdemir, Gül Nihal; Sayitoğlu, Müge; Eskazan, Ahmet Emre
    No Abstract Available
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    Lösemi modelinde tüm Genom RNA dizileme analiz algoritması geliştirilmesi
    (DergiPark, 2020) Sun, Eda; Sayitoğlu, Müge
    Amaç: RNA Dizileme teknolojisi gen anlatım farklılıkları ve kodlayan bölgedeki varyasyonlar, kodlama yapmayan küçük RNAların anlatımları ve gen füzyonlarının belirlenmesi ile bu farklılıkların nedenlerini sunabilmektedir. Ancak bu kadar enformatik bilgiler sunabilen bu teknolojinin analizlerinin yapılması ve yorumlanması oldukça zorludur. T- hücreli akut lenfoblastik lösemi (T-ALL) de prognostik öneme sahip ve hastalığın takibinde kullanılabilecek güvenilir bir genetik belirteç bulunmamakla birlikte, doğrudan tedavi protokolünü ve tedavide yararlanılacak yeni hedef proteinleri belirlemede esas olacak moleküler alt yapı ve sınıflandırma da bilinmemektedir. Gereç ve Yöntem: Biz de bu çalışmamızda, T-ALL gibi karmaşık bir genomik arka plana sahip lösemi hücrelerinde RNA-dizileme için en uygun enformatik iş akış algoritmasını oluşturmayı amaçladık. Bu çalışmada RNA dizileme ile Jurkat ve Molt 4 hücre hatları dizilenmiştir. Doğrulama ve karşılaştırma amacıyla açık veri bankalarından elde edilen sağlıklı timosit alt grupları ve T-ALL hasta (n=12) örnekleri (GSE48173) kullanılmıştır. Bulgular: Açık erişimli veri araçları ile gerçekleştirdiğimiz enformatik analizlerde doku spesifik alternatif kırpılma ürünlerinin kantitatif tayinini, spesifik gen varyasyonlarını ve global gen anlatım düzeylerini başarılı bir şekilde tespit ettik ve T-ALL hasta verisinde aynı yaklaşımları kullanarak doğrulama yaptık. Sonuç: Çalışmamızın sonucunda lösemi hastalarının veri analizinde kullanılabilecek uygun araçlar ve algoritma belirlenmiştir.
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    Lymphoma predisposing gene in an extended family: CD70 signaling defect
    (Springer/Plenum Publishers, 2020) Khodzhaev, Khusan; Bay, Sema Buyukkapu; Kebudi, Rejin; Altındirek, Didem; Kaya, Ayşenur; Erbilgin, Yücel; Ng, Özden Hatırnaz; Kıykım, Ayça; Erol Çipe, Funda; Şen Zengin, Feride; Fırtına, Sinem; Ng, Yuk Yin; Aksoy, Başak Adaklı; Sayitoğlu, Müge
    Genome-wide sequencing studies in pediatric cancer cohorts indicate that about 10% of patients have germline mutations within cancer predisposition genes. Within this group, primary immune deficiencies take the priority regarding the vulnerability of the patients to infectious agents and the difficulties of cancer management. On the other hand, early recognition of these diseases may offer specific targeted therapies and hematopoietic stem cell transplantation as an option. Besides therapeutic benefits, early diagnosis will provide genetic counseling for the family members. Within this context, an extended family with multiple consanguineous marriages and affected individuals, who presented with combined immune deficiency (CID) and/or Hodgkin lymphoma phenotype, were examined by exome sequencing. A pathogenic homozygous missenseCD70variation was detected (NM_001252.5:c332C>T) in concordance withCD70phenotype and familial segregation was confirmed.CD70variations in patients with CID and malignancy have very rarely been reported. This paper reports extended family with multiple affected members with CID and malignancy carrying a missenseCD70variation, and reviews the rare cases reported in the literature. Primary immune deficiencies appear to be a potential cause for pediatric cancers. Better focusing on these inborn disorders to prevent or make an early diagnosis of malignant transformation and reduce mortalities is important.
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    A novel candidate gene for predisposition of hodgkin lymphoma; Pregnan x receptor (PXR)
    (AMER SOC HEMATOLOGY, 2021) Kebudi, Rejin; Erbilgin, Yücel; Khodzhaev, Khusan; Sarıtaş, Merve; Bozkurt, Ceyhun; Sayitoğlu, Müge
    No Abstract Available
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    A novel foxn1 variant is identified in two siblings with nude severe combined immunodeficiency
    (Springer/Plenum Publishers, 2019) Fırtına, Sinem; Erol Cipe, Funda; Ng, Yuk Yin; Kiykim, Ayça; Ng, Özden Hatırnaz; Sudutan, Tuğce; Aydoğmuş, Çiğdem; Barış, Safa; Öztürk, Gülyüz; Aydıner, Elif; Özen, Ahmet; Sayitoğlu, Müge
    Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiencies (PIDs) caused by gene variants that lead to a failure of functional T cell development, with or without accompanying defects in the production of B and/or NK cells
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    Prognostic gene alterations and clonal changes in childhood B-ALL
    (Pergamon-Elsevier Science Ltd, 2019) Erbilgin, Yücel; Fırtına, Sinem; Mercan, Sevcan; Ng, Özden Hatırnaz; Karaman, Serap; Taşar, Orçun; Karakaş Zeybek, Didem; Celkan, Tulin Tiraje; Zengin, Emine; Sarper, Nazan; Yildirmak, Zeynep Yildiz; Şişko, Sinem; Özbek, Uğur; Sayitoğlu, Müge
    Genomic profiles of leukemia patients lead to characterization of variations that provide the molecular classification of risk groups, prediction of clinical outcome and therapeutic decisions. In this study, we examined the diagnostic (n = 77) and relapsed (n = 31) pediatric B-cell acute lymphoblastic leukemia (B-ALL) samples for the most common leukemia-associated gene variations CRLF2, JAK2, PAX5 and IL7R using deep sequencing and copy number alterations (CNAs) (CDKN2A/2B, PAX5, RB1, BTG1, ETV6, CSF2RA, IL3RA and CRLF2) by multiplex ligation proximity assay (MLPA), and evaluated for the clonal changes through relapse. Single nucleotide variations SNVs were detected in 19% of diagnostic 15.3% of relapse samples. The CNAs were detected in 55% of diagnosed patients; most common affected genes were CDKN2A/2B, PAX5, and CRLF2. Relapse samples did not accumulate a greater number of CNAs or SNVs than the cohort of diagnostic samples, but the clonal dynamics showed the accumulation/disappearance of specific gene variations explained the course of relapse. The CDKN2A/2B were most frequently altered in relapse samples and 32% of relapse samples carried at least one CNA. Moreover, CDKN2A/2B alterations and/or JAK2 variations were associated with decreased relapse-free survival. On the other hand, CRLF2 copy number alterations predicted a better survival rate in B-ALL. These findings contribute to the knowledge of CDKN2A/2B and CRLF2 alterations and their prognostic value in B-ALL. The integration of genomic data in clinical practice will enable better stratification of ALL patients and allow deeper understanding of the nature of relapse.
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    Status of IKZF1 deletions in diagnose and relapsed pediatric B-ALL patients
    (Springer, 2025) Erbilgin, Yücel; Fırtına, Sinem; Kırat, Elif; Khodzhaev, Khusan; Karakaş, Zeynep; Ünüvar, Ayşegül; Ocak, Süheyla; Celkan, Tülin Tiraje; Zengin, Emine; Aylan Gelen, Sema; Yıldırmak, Zeynep Yıldız; Toluk, Özlem; Hatırnaz Ng, Özden; Özbek, Uğur; Sayitoğlu, Müge
    IKZF1 deletions (Delta IKZF1) are common in precursor B-cell acute lymphoblastic leukemia (B-ALL) and are assumed to have a prognostic impact. We aimed to determine the prognostic implications of Delta IKZF1 and CRLF2 overexpression in pediatric B-ALL. Furthermore, we sought to compare the multiplex polymerase chain reaction (PCR) assay with standard multiplex ligand-dependent probe amplification (MLPA) methods to ascertain IKZF1 status in a clinical context. Seventy-nine diagnoses and 43 relapse B-ALL samples were evaluated for deletions of IKZF1 Delta 2-7, Delta 4-7, and Delta 4-8 by conventional PCR and then sequenced by targeted sequencing. Subsequently, MLPA analysis was performed for Delta IKZF1 detection, and CRLF2 expression was evaluated in 42 diagnose time B-ALL patients by QRT-PCR. Delta IKZF1 was detected in 10 out of 79 diagnose samples (12.66%) and eight of the 43 first relapsed materials (18.60%). Our results revealed no association between survival outcomes with Delta IKZF1 or CRLF2 overexpression status in pediatric B-ALL patients. However, we found Delta IKZF1 was more frequent among relapsed samples, and the deletions showed consistency between diagnose-first/second relapse pairs of samples. These results suggest that Delta IKZF1 may contribute to the development of treatment failure in B-ALL. Furthermore, we demonstrated methodological adjustments in conventional PCR and MLPA for selected alterations in Delta IKZF1.
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    Tanısı zor tek gen hastalıklarında hedefe yönelik yeni nesil dizileme panel tasarımı: primer immün yetersizlik örneği
    (DergiPark, 2020) Fırtına, Sinem; Hatırnaz Ng, Özden; Sayitoğlu, Müge; Yin Ng, Yuk
    Amaç: Yeni nesil dizileme teknolojileri bugün çok sayıda aday genin, genomun tüm kodlayan bölgelerinin hatta tüm genomun analizini tek seferde ve kısa süre içerisinde düşük maliyet ve yüksek hassasiyette, güvenilir bir şekilde mümkün kılmaktadır. Hedefe yönelik yeni nesil dizileme sistemleri genomda sadece belirli bölgenin dizilenmesine imkan veren, tüm genom dizilemelere göre uygulaması ve analizi daha kolay, hızlı ve yüksek güvenirlilikte bir yöntem olarak pek çok rutin genetik tanı uygulamalarında yerini bulmuştur. Gereç ve Yöntem: Çalışmamızda primer immün yetersizliklerin en yaygın grubu olan primer antikor yetersizlikleri (PAY) ve en ağır seyirli grubu ağır kombine immün yetersizlikler (AKİY) için hastalık ile ilişkili olduğu bilinen genleri kapsayan PZR temelli genetik tanı panelleri geliştirilmiş ve ortaya çıkan yüksek verinin yorumlanması için bir analiz akışı oluşturulmuştur. Bulgular: Tasarlanan paneller ile toplam 112 hasta (PAY:64, AKİY:48) dizilenmiş ve AKİY hastalarının %58’i ve PAY hastalarının %14,2’sinde hastalık ile ilişkili varyantlar tespit edilmiştir. Tüm varyantlar Sanger dizileme ile doğrulanarak oluşturulan moleküler tanı panellerinin ve analiz algoritmasının doğruluğu kontrol edilmiştir. Sonuç: Hedefe yönelik yeni nesil dizileme panellerinin hedeflenen bölgeye uygun olarak doğru yöntemle tasarlanması ve çıkan ham datanın doğru iş akışı ile analiz edilmesi panelin başarısını arttırmaktadır.
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    Zinc finger protein 384 ( ZNF384) impact on childhood mixed phenotype acute leukemia and B-cell precursor acute lymphoblastic leukemia
    (Taylor and Francis, 2022) Sudutan, Tuğce; Erbilgin, Yücel; Hatırnaz, Özden; Karaman, Serap; Karakaş, Zeynep; Küçükcankurt, Fulya; Celkan, Tülin Tiraje; Timur, Çetin; Özdemir, Gül Nihal; Hacısalihoglu, Sadan; Aylan Gelen, Sema; Sayitoğlu, Müge
    B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous malignancy and consists of several genetic abnormalities. Some of these abnormalities are used in clinics for risk calculation and treatment decisions. Patients with ZNF384 rearrangements had a distinct expression profile regardless of their diagnosis, BCP-ALL or mixed phenotype acute leukemia (MPAL) and defined as a new subtype of ALL. In this study, we screened 42 MPAL and 91 BCP-ALL patients for the most common ZNF384 fusions; ZNF384::TCF3, ZNF384::EP300 and ZNF384::TAF15 by using PCR. We identified ZNF384 fusions in 9.5% of MPAL and 7.6% of BCP-ALL. A novel breakpoint was identified in ZNF384::TCF3 fusion in one BCP-ALL patient. T-myeloid MPAL patients showed significantly lower ZNF384 expression compared to lymphoid groups. Patients with ZNF384r had intermediate survival rates based on other subtypes. Prognostic and patient-specific treatment evaluation of ZNF384 fusions in both ALL and MPAL might help to improve risk characterization of patients.