全基因组测序和单细胞转录组学发现 KMT2D 是垂体腺瘤的潜在新驱动因素

Maxime Brunner, Jenny Meylan-Merlini, Maude Muriset, Sergey Oreshkov, Andrea Messina, Mahmoud Messerer, Roy Thomas Daniel, Ekkehard Hewer, Jean Philippe Brouland, Federico Santoni
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引用次数: 0

摘要

垂体是内分泌系统的主要组成部分,也是激素产生和分泌的主要控制者。与其他器官的肿瘤形成不同,垂体神经内分泌肿瘤(Pituitary Neuroendocrine Tumors,PitNETs)在人群中的发病率很高(16%),而且由于不明原因,几乎完全是良性的。迄今为止,很少有基因被确定为 PitNET 的驱动基因,如体细胞瘤中的 GNAS 和皮质细胞瘤中的 USP8。通过全基因组测序,我们在一位50多岁的躯体-内脏混合瘤患者身上发现了一个潜在的新型驱动基因--组蛋白甲基转移酶KMT2D。生殖细胞和肿瘤的覆盖率显示了广泛的染色体改变。肿瘤的单细胞 RNA 测序显示,与健康参照物相比,已知的致瘤通路出现上调,免疫浸润特征也与其他 PitNET 不同,与腺瘤相比,更接近于癌的特征。全基因组DNA甲基化分析发现了792个不同的甲基化区域,包括免疫相关基因SPON2启动子的显著低甲基化。我们的研究结果表明,被认为是安静和非侵袭性的肿瘤可能与转移性癌症具有共同的驱动因素、特征和表观遗传学改变,这就提出了控制其平衡的生物学机制的问题。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Whole Genome Sequencing and single-cell transcriptomics identify KMT2D as a potential new driver for pituitary adenomas
The pituitary gland is a main component of the endocrine system and a master controller of hormone production and secretion. Unlike neoplastic formation in other organs, Pituitary Neuroendocrine Tumors (PitNETs) are frequent in the population (16%) and, for unknown reasons, almost exclusively benign. So far, few genes have been identified as drivers for PitNETs, such as GNAS in somatotroph tumors and USP8 in corticotroph tumors. Using whole genome sequencing, we uncover a potential novel driver, the histone methyltransferase KMT2D, in a patient in his 50s suffering from a mixed somato-lactotroph tumor. Coverage ratio between germline and tumor revealed extensive chromosomal alterations. Single-cell RNA sequencing of the tumor shows up-regulation of known tumorigenic pathways compared to a healthy reference, as well as a different immune infiltration profile compared to other PitNETs, more closely resembling the profile of carcinomas than adenomas. Genome-wide DNA methylation analysis identified 792 differentially methylated regions, including notable hypomethylation in the promoter of SPON2, an immune-related gene. Our results show that tumors considered as quiet and non-aggressive can share drivers, features, and epigenetic alterations with metastatic forms of cancer, raising questions about the biological mechanisms controlling their homeostasis.
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