Abstract：
Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors that co-express GIPR and NR5A1 (SF-1). SF-1 expression was verified with immunohistochemistry. Transcriptomic group 2 tumors are the most common (46%) and include mainly GNAS-mutated, densely granulated somatotroph and mixed PitNETs. They have a smaller size and express favorable prognosis-related genes. Transcriptomic group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly. Ghrelin signaling is implicated in their pathogenesis. They have an unfavorable gene expression profile and higher invasive growth rate.
摘要：
生长激素分泌过多导致肢端肥大症，主要由生长激素垂体神经内分泌肿瘤（PitNET）引起。导致肢端肥大症的肿瘤在组织学上是不同的。我们的目的是确定各种生长激素PitNETs的转录组学谱，并评估差异基因表达的临床意义。总共对48个肿瘤进行了RNA测序，而用qRT-PCR在134个肿瘤中评估了所选基因的表达。全转录组分析揭示了三个转录组的生长素PitNETs。它们在许多基因的表达方面不同，包括与生长激素分泌有关的基因和已知的预后基因。转录组亚组可以通过确定标记基因的表达来区分。对整个患者队列的分析证实了肿瘤分子亚型之间的差异。转录组1包括~20%的GNAS突变阴性的肢端肥大症患者，主要是共表达GIPR和NR5A1（SF-1）的致密颗粒肿瘤。用免疫组织化学证实SF-1的表达。转录组2组肿瘤是最常见的（46％），主要包括GNAS突变，浓密的肉芽肿和混合的PitNETs。它们具有较小的尺寸并表达有利的预后相关基因。转录组3包括主要是稀疏颗粒的体细胞营养PitNETs，其GNAS突变频率低，导致约35％的肢端肥大症。Ghrelin信号传导与它们的发病机理有关。它们具有不利的基因表达谱和较高的侵入性生长速率。
