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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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    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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    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.