侵袭性垂体神经内分泌肿瘤的纵向多组学分析：比较同一患者的原发性和复发性肿瘤，揭示基因组稳定性和异质转录组谱以及代谢途径的改变。
Longitudinal multiomics analysis of aggressive pituitary neuroendocrine tumors: comparing primary and recurrent tumors from the same patient, reveals genomic stability and heterogeneous transcriptomic profiles with alterations in metabolic pathways.
发表日期：2024 Aug 31
作者：
Keiko Taniguchi-Ponciano, Silvia Hinojosa-Alvarez, Jesus Hernandez-Perez, Rocio A Chavez-Santoscoy, Ilan Remba-Shapiro, Gerardo Guinto, Erika Magallon-Gayon, Benjamin Telles-Ramirez, Rodrigo Ponce de Leon-Conconi, Sandra Vela-Patiño, Sergio Andonegui-Elguera, Amayrani Cano-Zaragoza, Florencia Martinez-Mendoza, Jacobo Kerbel, Marco Loza-Mejia, Juan Rodrigo-Salazar, Alonso Mendez-Perez, Cristina Aguilar-Flores, Antonieta Chavez-Gonzalez, Elenka Ortiz-Reyes, Erick Gomez-Apo, Laura C Bonifaz, Daniel Marrero-Rodriguez, Moises Mercado
来源：
Acta Neuropathologica Communications
摘要：
鞍区肿块中绝大多数为垂体神经内分泌肿瘤（PitNET）。有些表现出攻击性，生长迅速并侵入周围组织，复发率和治疗耐药性很高。我们的目标是建立同一患者的原发性和复发性肿瘤随时间变化的基因组、转录组和甲基组进化模式。因此，我们对同一患者的侵袭性、原发性和复发性 PitNET 进行了转录组和外显子组测序以及甲基化组微阵列。原发性和复发性肿瘤显示出相似的外显子组特征，可能表明随着时间的推移基因组保持稳定。相比之下，原发性和复发性 PitNET 的转录组并不相似。促性腺激素、沉默促肾上腺皮质激素以及转移性促肾上腺皮质激素和生长激素PitNET分别表达与脂肪酸生物合成和代谢、磷脂酰肌醇信号传导、甘油磷脂和磷脂酶D信号传导相关的基因。二酰基甘油激酶γ (DGKG) 是甘油磷脂代谢和磷脂酰肌醇信号通路中的关键酶，在原发性和复发性 PitNET 之间表达存在差异。这些改变似乎不是由 DNA 甲基化调节的，而是由几种转录因子调节的。分子对接表明，用于治疗慢性淋巴细胞和急性淋巴细胞白血病的小分子酪氨酸激酶抑制剂达沙替尼可以靶向DGKG。达沙替尼诱导 GH3 细胞凋亡并减少增殖。我们的数据表明垂体肿瘤的发生可能是由转录组异质克隆驱动的，我们描述了针对侵袭性和复发性 PitNET 的替代药物疗法。© 2024。作者。
Pituitary neuroendocrine tumors (PitNET) represent the vast majority of sellar masses. Some behave aggressively, growing rapidly and invading surrounding tissues, with high rates of recurrence and resistance to therapy. Our aim was to establish patterns of genomic, transcriptomic and methylomic evolution throughout time in primary and recurrent tumors from the same patient. Therefore, we performed transcriptome- and exome-sequencing and methylome microarrays of aggressive, primary, and recurrent PitNET from the same patient. Primary and recurrent tumors showed a similar exome profile, potentially indicating a stable genome over time. In contrast, the transcriptome of primary and recurrent PitNET was dissimilar. Gonadotroph, silent corticotroph, as well as metastatic corticotroph and a somatotroph PitNET expressed genes related to fatty acid biosynthesis and metabolism, phosphatidylinositol signaling, glycerophospholipid and phospholipase D signaling, respectively. Diacylglycerol kinase gamma (DGKG), a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways, was differentially expressed between primary and recurrent PitNET. These alterations did not seem to be regulated by DNA methylation, but rather by several transcription factors. Molecular docking showed that dasatinib, a small molecule tyrosine kinase inhibitor used in the treatment of chronic lymphocytic and acute lymphoblastic leukemia, could target DGKG. Dasatinib induced apoptosis and decreased proliferation in GH3 cells. Our data indicate that pituitary tumorigenesis could be driven by transcriptomically heterogeneous clones, and we describe alternative pharmacological therapies for aggressive and recurrent PitNET.© 2024. The Author(s).