PO.MCB08.05 · 分子与细胞生物学
一名接受TNF-alpha抑制剂治疗患者的IDH野生型胶质母细胞瘤基因组图景:对风险分层和治疗决策的意义
Genomic landscape of IDH-wild-type glioblastoma in a patient treated with TNF-alpha inhibitor: Implications for risk stratification and therapeutic decision-making
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摘要 Abstract
中文摘要
背景:
TNF-alpha抑制剂(如阿达木单抗)被广泛用于自身免疫性疾病,但其对遗传易感个体肿瘤发生的长期影响仍不明确。多形性胶质母细胞瘤(GBM)是一种侵袭性的IDH野生型肿瘤,具有明确的分子驱动因素,但对TNF-alpha抑制剂治疗患者所发生GBM的基因组表征仍极为有限。我们研究了一例在序贯接受甲氨蝶呤、柳氮磺吡啶、阿达木单抗和托法替尼治疗后发生的GBM的基因组特征,以探索免疫调节与肿瘤演变之间可能的机制联系。
方法:
肿瘤组织在两个独立的临床实验室进行了免疫组织化学、靶向二代测序和拷贝数分析。基因组结果在TNF-alpha通路生物学、肿瘤微环境(TME)相互作用以及与GBM进展相关的已知分子通路的背景下进行解读。
结果:
肿瘤表现出GFAP和OLIG阳性、Ki-67为45%以及强p53表达(>90%)。基因组分析揭示了IDH野生型GBM的标志性改变,包括CDKN2A/B缺失、PTEN缺失和TP53突变。一些不寻常的变异包括KDM6A移码变异、意义未明的意外ATRX突变以及PDPK1缺失。值得注意的是,该肿瘤缺乏TERT启动子突变——该突变存在于大多数IDH野生型GBM中——提示存在替代性端粒维持通路。PTEN缺失、TP53突变和CDKN2A/B缺失的组合提示一种与TME内免疫逃逸相关的高度侵袭性分子表型。若干改变的通路与TNF-alpha信号相交叉,提示在TNF-alpha阻断下肿瘤-免疫相互作用可能发生改变。
结论:
本分析在一例经长期TNF-alpha靶向治疗后发生的GBM中鉴定出经典和非典型的基因组改变。TERT启动子突变的缺失和不寻常ATRX变异的存在提示一条非标准的演变轨迹。尽管无法确立因果关系,但与TNF-alpha抑制剂暴露的时间关联,加上TNF-alpha生物学、PTEN/TP53信号和免疫调节之间的通路重叠,值得进一步研究。这些发现强调了在启动TNF-alpha抑制剂治疗前进行基因组风险分层和考虑种系易感性的重要性,以及对生物制剂治疗期间出现的肿瘤进行系统性基因组分析的必要性。
查看英文原文 English abstract
Background:
TNF-alpha inhibitors, such as adalimumab, are widely used for autoimmune diseases, yet their long-term impact on tumorigenesis in genetically susceptible individuals remains unclear. Glioblastoma multiforme (GBM) is an aggressive IDH-wild-type tumor with well-defined molecular drivers, but genomic characterization of GBM arising in TNF-alpha inhibitor-treated patients remains extremely limited. We investigated the genomic profile of a GBM that developed after sequential methotrexate, sulfasalazine, adalimumab, and tofacitinib therapy to explore possible mechanistic links between immunomodulation and tumor evolution.
Methods:
Tumor tissue underwent immunohistochemistry, targeted next-generation sequencing, and copy-number analysis at two independent clinical laboratories. Genomic results were interpreted in the context of TNF-alpha pathway biology, tumor microenvironment (TME) interactions, and known molecular pathways associated with GBM progression.
Results:
The tumor demonstrated GFAP and OLIG positivity, Ki-67 of 45%, and strong p53 expression (>90%). Genomic profiling revealed hallmark alterations of IDH-wild-type GBM, including CDKN2A/B deletions, PTEN deletion, and TP53 mutation. Some unusual variants included a KDM6A frameshift variant, an unexpected ATRX mutation with uncertain pathogenicity, and PDPK1 loss. Notably, the tumor lacked a TERT promoter mutation-present in the majority of IDH-wild-type GBMs-suggesting alternative telomere-maintenance pathways. The combination of PTEN loss, TP53 mutation, and CDKN2A/B deletion indicated a highly aggressive molecular phenotype associated with immune evasion within the TME. Several altered pathways intersect with TNF-alpha signaling, raising the possibility of altered tumor-immune interactions under TNF-alpha blockade.
Conclusions:
This analysis identifies both canonical and atypical genomic alterations in a GBM arising after prolonged TNF-alpha-targeted therapy. The absence of a TERT promoter mutation and the presence of an unusual ATRX variant suggest a nonstandard evolutionary trajectory. Although causality cannot be established, the temporal association with TNF-alpha inhibitor exposure, combined with pathway overlap between TNF-alpha biology, PTEN/TP53 signaling, and immune regulation, warrants further investigation. These findings highlight the importance of genomic risk stratification and consideration of germline predisposition before initiating TNF-alpha inhibitors, as well as the need for systematic genomic profiling of tumors emerging during biologic therapy.
利益披露 Disclosure
S. Mohapatra, None..
N. Ganesan, None.