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。

IF 1.6 4区 医学 Q3 GENETICS & HEREDITY
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引用次数: 0

摘要

霍奇金淋巴瘤(HL)是青少年中最常见的癌症。有霍奇金淋巴瘤家族史会增加其他家庭成员罹患霍奇金淋巴瘤的风险。鉴定 HL 的遗传易感性变异对了解疾病的病因、预后和治疗反应非常重要。NF-κB 通路的异常激活是 HL 的标志性特征,有助于 HL 特征性恶性细胞的存活和增殖。我们通过全外显子组测序,对一个有多个确诊 HL 患者同胞的近亲结婚家庭进行了研究。我们发现了一个 PXR 配体结合域的种系同源变异(NM_003889.3:c.811G>A, p. (Asp271Asn)),该变异被预测工具归类为致病性,并在 HL 病例中遗传。通过定量实时聚合酶链式反应(qRT-PCR)发现,与杂合子携带者相比,同源变异携带者的 PXR 表达增加,对患者福尔马林固定石蜡包埋组织的免疫荧光染色显示 PXR 上调,尤其是在霍奇金里德/斯特恩伯格(HRS)细胞中。与 PXR 野生型 HL、杂合子和对照组相比,PXR 同源变异型患者的表达量明显较高(分别为 p = 0.0001、p = 0.0004 和 p = 0.0001)。与 PXR 野生型 HRS 细胞相比,PXR 同源型 HRS 细胞的 PXR 表达量明显更高(P -/-小鼠模型发生多灶性淋巴瘤,NF-κB 表达异常增加,炎症持续存在。要阐明 PXR 在 HL 发病机制中的确切作用机制,还需要进一步的功能研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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来源期刊
CiteScore
4.10
自引率
0.00%
发文量
193
审稿时长
66 days
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.
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