MicroRNA-371-373 cluster and methylome analysis suggests that a subset of 'somatic-type' malignancies arising in germ cell tumors may originate in yolk sac tumor components.

IF 5.6 2区 医学 Q1 ONCOLOGY
João Lobo, Nuno Tiago Tavares, Diana Fonseca, Carmen Jerónimo, Rui Henrique, Nicolas Wyvekens, Yiying Yang, Matija Snuderl, Fiona Maclean, Jennifer Gordetsky, Christopher Dm Fletcher, Michelle S Hirsch, Jason L Hornick, Muhammad T Idrees, Katrina Collins, Laura Warmke, Thomas M Ulbright, Andres M Acosta
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引用次数: 0

Abstract

Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)-371-373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT-SM samples from individual tumors) were assessed for miR-371-373 expression by RT-qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR-371-373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR-371-373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome-wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and 'somatic-type' components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to 'somatic-type' phenotypes. Gene-level and pathway-level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial-to-mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic-type histology, suggesting mechanisms of progression from conventional to 'somatic' phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent 'intermediate' phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

MicroRNA-371-373聚类和甲基组分析表明,生殖细胞肿瘤中出现的一部分“躯体型”恶性肿瘤可能起源于卵黄囊肿瘤成分。
生殖细胞肿瘤(gct)中出现的躯体型恶性肿瘤(SMs)是一种侵袭性肿瘤,对全身治疗具有抵抗性。大多数在化疗后被诊断为转移部位;然而,它们在原发性睾丸gct中也有充分的记录。从历史上看,SMs被认为起源于畸胎瘤的组成部分,这些组成部分获得的分子改变相当于它们真正的体细胞对偶物的特征。然而,最近的研究表明,SMs通常缺乏在类似的体细胞肿瘤中看到的标志性分子改变。此外,临床病理和分子数据表明,一个亚群可能来自卵黄囊肿瘤(YST),而不是畸胎瘤。在这项研究中,我们通过比较microRNA (miR)-371-373的表达和基因组甲基化谱,评估了gct的常规组织学类型与SMs之间的关系。通过RT-qPCR评估共96个样本(包括来自单个肿瘤的多个配对常规GCT-SM样本)的miR-371-373表达,并使用临床验证的方法评估基因组DNA甲基化。miR-371-373在常规gct中的表达高于在SMs中的表达(被认为是包含所有组织学亚型的单一类别)。然而,miR-371-373在SMs中的表达是异质性的,在肉瘤样YST (SYST)和腺肿瘤中的表达水平明显高于其他SMs。基因组DNA甲基化分析表明,SMs(被认为是单一类别)没有形成一个明显的集群。相反,他们被分成多个与组织学不完全对应的集群,通常包括传统的gct。全基因组甲基化评估显示,SMs中高甲基化区域的丰度高于常规gct。对配对的常规GCT和“体细胞型”成分进行分析,这些成分不符合从单个肿瘤解剖的SMs的大小标准,根据组织学显示分离,这表明表观遗传过程在从常规GCT到“体细胞型”表型的转变中起作用。基因水平和通路水平分析发现,MAPK/RAS信号、有丝分裂/增殖、向神经组织/神经外胚层分化、上皮到间质转化和DNA修复是具有躯体型组织学成分的关键差异调节过程,这提示了GCT从常规表型向“躯体”表型进展的机制。这些结果支持了一种假设,即SMs的一个子集源于YST,并表明一些亚型(如SYST)可能代表“中间”表型。此外,对SM中差异甲基化启动子区域的分析发现了可能导致gct“体细胞转化”的基因和生物过程。©2025作者。《病理学杂志》由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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