利用DNA甲基化分析扩大 "融合阳性 "病例的基因谱,在肺泡横纹肌肉瘤中发现新型PAX3::MAML3融合。

IF 7.1 1区 医学 Q1 PATHOLOGY Modern Pathology Pub Date : 2024-08-13 DOI:10.1016/j.modpat.2024.100594
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引用次数: 0

摘要

伴有FOXO1基因重排的肺泡横纹肌肉瘤(ARMS)是一种侵袭性小儿横纹肌肉瘤亚型,在预后上有别于胚胎性横纹肌肉瘤和融合阴性ARMS。在此,我们报告了两例伴有PAX3::MAML3融合的ARMS病例。这两例肿瘤分别发生在一名婴儿和一名青少年身上,均为 IV 期转移性疾病(根据儿童肿瘤组织分期系统)。从组织学上看,两个病例均为小圆形蓝细胞瘤,呈模糊的巢状和实性片状排列,desmin和myogenin呈弥漫性阳性。通过甲基化分析和无监督聚类分析,这些肿瘤与典型FOXO1重排的ARMS和变异PAX3::NCOA1/INO80D融合的ARMS聚类,但不与PAX3::MAML3/NCOA2/FOXO1/YAP1融合的双型鼻窦肉瘤(BSNS)聚类,也不与包括胚胎性横纹肌肉瘤在内的其他小圆形蓝细胞肿瘤聚类。ARMS和BSNS的不同甲基化基因高度富集于参与肌生成的基因中,其中21%的基因与PAX3::FOXO1融合转录因子的靶基因重叠。在开始接受长春新碱/放线菌素/环磷酰胺化疗后的随访中,肿瘤出现了部分和完全的临床反应,这与典型的FOXO1重排的ARMS的前期化疗反应性一致。我们的结论是,PAX3::MAML3 是 ARMS 的一种新型变异融合体,它显示出不同于 BSNS 的甲基化特征,尽管具有相似的 PAX3 融合。这些发现凸显了甲基化分析在对非典型融合的 ARMS 进行分类时的实用性。
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Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of “Fusion-Positive” Cases

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Here, we report 2 cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children’s Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic FOXO1 rearrangements and ARMS with variant PAX3::NCOA1/INO80D fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with PAX3::MAML3/NCOA2/FOXO1/YAP1 fusions nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical responses, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic FOXO1 rearrangement. We conclude that PAX3::MAML3 is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar PAX3 fusions. These findings highlight the utility of methylation profiling in classifying ARMS with noncanonical fusions.

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来源期刊
Modern Pathology
Modern Pathology 医学-病理学
CiteScore
14.30
自引率
2.70%
发文量
174
审稿时长
18 days
期刊介绍: Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.
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