{"title":"在两个兄弟姐妹中,一种新型生殖系孕烷 X 受体 (PXR) 变异易导致霍奇金淋巴瘤。","authors":"","doi":"10.1016/j.ejmg.2024.104975","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div><div>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 <em>PXR</em> 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.</div><div>Patients with homozygous <em>PXR</em> variant showed significantly high expression compared to <em>PXR</em> wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). <em>PXR</em> homozygous HRS cells had significantly higher PXR expression compared to <em>PXR</em> wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous <em>PXR</em> HRS cells showed increased PXR expression in nucleus (p < 0.001).</div><div>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 <em>PXR</em> HL cases. This study provided clinical evidence to previously reported <em>Sxr</em><sup><em>−/−</em></sup> 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.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6000,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings\",\"authors\":\"\",\"doi\":\"10.1016/j.ejmg.2024.104975\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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.</div><div>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 <em>PXR</em> 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.</div><div>Patients with homozygous <em>PXR</em> variant showed significantly high expression compared to <em>PXR</em> wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). <em>PXR</em> homozygous HRS cells had significantly higher PXR expression compared to <em>PXR</em> wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous <em>PXR</em> HRS cells showed increased PXR expression in nucleus (p < 0.001).</div><div>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 <em>PXR</em> HL cases. This study provided clinical evidence to previously reported <em>Sxr</em><sup><em>−/−</em></sup> 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.</div></div>\",\"PeriodicalId\":11916,\"journal\":{\"name\":\"European journal of medical genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2024-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of medical genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1769721224000673\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of medical genetics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1769721224000673","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings
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.
期刊介绍:
The European Journal of Medical Genetics (EJMG) is a peer-reviewed journal that publishes articles in English on various aspects of human and medical genetics and of the genetics of experimental models.
Original clinical and experimental research articles, short clinical reports, review articles and letters to the editor are welcome on topics such as :
• Dysmorphology and syndrome delineation
• Molecular genetics and molecular cytogenetics of inherited disorders
• Clinical applications of genomics and nextgen sequencing technologies
• Syndromal cancer genetics
• Behavioral genetics
• Community genetics
• Fetal pathology and prenatal diagnosis
• Genetic counseling.