长期多组学分析侵袭性垂体神经内分泌肿瘤：比较同一患者的原发和复发肿瘤，揭示基因组稳定性与异质性转录谱变化及代谢通路的改变

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

Acta Neuropathologica Communications

影响因子:5.7

分区:医学1区 Top / 神经科学1区

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

DOI: 10.1186/s40478-024-01796-x

摘要

垂体神经内分泌肿瘤（PitNET）占垂体肿块的绝大多数。一些表现出侵袭性，生长迅速并侵入周围组织，复发率高且对治疗抗性。我们的目标是建立同一患者的原发与复发肿瘤在基因组、转录组和甲基组演变的模式。因此，我们对同一患者的侵袭性原发与复发PitNET进行了转录组和外显子组测序及甲基组微阵列分析。结果显示，原发与复发肿瘤的外显子组特征相似，可能表明基因组在时间上的稳定性。而转录组则表现出明显差异。促性腺细胞、无泪皮质细胞，以及转移性皮质细胞和生长激素细胞PitNET都表达与脂肪酸生物合成和代谢、磷脂酰肌醇信号通路、甘油磷脂和磷脂酶D信号通路相关的基因。甘油酰基转移酶γ（DGKG），作为甘油磷脂代谢和磷脂酰肌醇信号通路的关键酶，在原发与复发PitNET中的表达存在差异。这些变化似乎不是由DNA甲基化调控，而是由多种转录因子调控。分子对接分析显示，小分子酪氨酸激酶抑制剂达沙替尼（Dasatinib）可以靶向DGKG。达沙替尼诱导GH3细胞的凋亡并降低其增殖。我们的研究提示，垂体肿瘤的发生可能由转录组异质性克隆驱动，并提出了针对侵袭性和复发性PitNET的替代药物治疗策略。

Abstract

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.