A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings

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dc.authorscopusidCeyhun Bozkurt / 6602784315
dc.authorwosidCeyhun Bozkurt / AAL-5043-2021
dc.contributor.authorKhodzhaev, Khusan
dc.contributor.authorSudutan, Tuğce
dc.contributor.authorErbilgin, Yücel
dc.contributor.authorSarıtaş, Merve
dc.contributor.authorYeğen, Gülçin
dc.contributor.authorBozkurt, Ceyhun
dc.contributor.authorSayitoğlu, Müge
dc.contributor.authorKebudi, Rejin
dc.date.accessioned2025-04-16T20:26:53Z
dc.date.available2025-04-16T20:26:53Z
dc.date.issued2024
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü
dc.description.abstractHodgkin'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
dc.description.sponsorshipThis study was funded by Scientific Research Projects Coordination Unit of Istanbul University, Project number: TDK-2022-38816, TDK-2020-37127, TSA-2023-39470 and General Directorate of Development Agencies, Istanbul Development Agency Project number: TR10/22/TNH/0001.
dc.identifier.citationKhodzhaev, K., Sudutan, T., Erbilgin, Y., Saritas, M., Yegen, G., Bozkurt, C., ... & Kebudi, R. (2024). A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings. European Journal of Medical Genetics, 72, 104975.
dc.identifier.doi10.1016/j.ejmg.2024.104975
dc.identifier.issn17697212
dc.identifier.pmid39322061
dc.identifier.scopusqualityQ3
dc.identifier.urihttp://dx.doi.org/10.1016/j.ejmg.2024.104975
dc.identifier.urihttps://hdl.handle.net/20.500.12713/6077
dc.identifier.volume72
dc.identifier.wosWOS:001328777300001
dc.identifier.wosqualityQ3
dc.indekslendigikaynakScopus
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.institutionauthorBozkurt, Ceyhun
dc.institutionauthoridCeyhun Bozkurt / 0000-0001-6771-9894
dc.language.isoen
dc.publisherElsevier Masson s.r.l.
dc.relation.ispartofEuropean Journal of Medical Genetics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGermline Predisposition
dc.subjectHRS Cell
dc.subjectLymphoma
dc.subjectNF-κB
dc.subjectPXR
dc.titleA novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings
dc.typeArticle

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