Acta Neuropathol|M Beatriz Lopes团队揭示垂体后叶肿瘤的遗传学和表观遗传学特征

2022年8月4日 0条评论 238次阅读 0人点赞

最新细胞功能及机制文献分享

垂体细胞瘤（PITUI）、颗粒细胞瘤（GCT）和梭形细胞嗜酸细胞瘤（SCO）是垂体后叶的罕见肿瘤，在组织学上，它们可能难以区分。2016年WHO中枢神经系统肿瘤分类将其列为独立实体瘤，并因其低级别组织学外观、缓慢生长和良性临床过程等特点而被指定为WHO Ⅰ级肿瘤，目前，国际上仍没有这些罕见肿瘤的流行病学数据。2021年10月18日，美国弗吉尼亚州夏洛茨维尔弗吉尼亚大学卫生系统病理学、神经病理学系M Beatriz Lopes团队在Acta Neuropathologica上发表了题为“Genetic and epigenetic characterization of posterior pituitary tumors”的研究论文。在本研究中，团队通过对47个肿瘤（14个PITUI、12个GCT、21个SCO）进行了靶向下一代测序、DNA甲基化分析和拷贝数分析，以研究分子特征并探索具有临床意义的肿瘤亚分类的可能性。结果证实，首先，垂体后叶肿瘤之间的DNA甲基化差异非常微妙；其次，拷贝数改变可能对首次诊断识别复发时间较短的肿瘤具有价值；再者，很大一部分垂体后叶肿瘤可潜在靶向MAPK/PI3K通路；最后，团队还建议将垂体来源的肿瘤重新分类为三个临床相关的新亚型，即一组代表先前建立的颗粒细胞肿瘤，由颗粒细胞组织学、可识别致癌突变的稀缺性和良好的结果来定义，其他两组均代表梭形细胞嗜酸细胞瘤和垂体细胞瘤组织学的混合，具有SCO或PITUI组织学，但根据染色体拷贝数分布可分为有利组（无拷贝数变化）和较差组（存在拷贝数不平衡），后两组都具有代表潜在治疗靶点的复发性MAPK/PI3K基因改变。

《Acta Neuropathol|M Beatriz Lopes团队揭示垂体后叶肿瘤的遗传学和表观遗传学特征》

图组织学、突变频率、染色体不平衡和三种组织分子亚型关系的示意图。

期刊及DOI号

Acta Neuropathol. 2021 Oct 18.

doi: 10.1007/s00401-021-02377-1.

题目

Genetic and epigenetic characterization of posterior pituitary tumors

摘要

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n=23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n=16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p=0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.