IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
Clin Endocrinol (Oxf). 2022 Dec;97(6):763-772. doi: 10.1111/cen.14827. Epub 2022 Oct 7.
To profile clinically non-aggressive and aggressive pituitary adenomas (PAs)/pituitary neuroendocrine tumours (PitNETs) and pituitary carcinomas for somatic mutations and epigenetic alterations of genes involved in cell proliferation/differentiation, microRNAs (miRNA)/long noncoding RNA (LncRNA)-post-transcriptional regulators and therapy targets.
Retrospective observational study.
A total of 64 non-aggressive and 41 aggressive PAs/PitNETs and 6 pituitary carcinomas treated by endoscopic surgery with ≥1-year follow-up were included. Somatic mutations of 17 genes and DNA methylation of 22 genes were assessed. Ten normal pituitaries were used as control.
We found at least one mutation in 17 tumours, including 6/64 non-aggressive, 10/41 aggressive PAs/PitNETs, and 1/6 pituitary carcinoma. AIP (N = 6) was the most frequently mutated gene, followed by NOTCH (4), and TP53 (3). Hypermethylation of PARP15, LINC00599, ZAP70 was more common in aggressive than non-aggressive PAs/PITNETs (p < .05). Lower levels of methylation of AIP, GNAS and PDCD1 were detected in aggressive PAs/PITNETs than non-aggressive ones (p < .05). For X-linked genes, males presented higher level of methylation of FLNA, UXT and MAGE family (MAGEA11, MAGEA1, MAGEC2) genes in aggressive vs. non-aggressive PAs/PITNETs (p < .05). In pituitary carcinomas, methylation of autosomal genes PARP15, LINC00599, MIR193 and ZAP70 was higher than in PAs/PITNETs, while X-linked genes methylation level was lower.
Somatic mutations and methylation levels of genes involved in cell proliferation/differentiation, miRNA/LncRNA-post-transcriptional regulators and targets of antineoplastic therapies are different in non-aggressive and in aggressive PAs/PitNETs. Methylation profile also varies according to gender. Combined genetic-epigenetic analysis, in association with clinico-radiological-pathological data, may be of help in predicting PA/PitNET behaviour.
分析临床非侵袭性和侵袭性垂体腺瘤（PA）/垂体神经内分泌肿瘤（PitNET）和垂体癌中涉及细胞增殖/分化、microRNA（miRNA）/长链非编码 RNA（LncRNA）-转录后调控因子和治疗靶点的基因的体细胞突变和表观遗传改变。
回顾性观察性研究。
共纳入 64 例非侵袭性和 41 例侵袭性 PA/PitNET 以及 6 例经内镜手术治疗的垂体癌患者，随访时间均≥1 年。评估了 17 个基因的体细胞突变和 22 个基因的 DNA 甲基化。10 个正常垂体作为对照。
我们在 17 个肿瘤中发现了至少一个突变，包括 6/64 个非侵袭性、10/41 个侵袭性 PA/PitNET 和 1/6 个垂体癌。AIP（N=6）是最常突变的基因，其次是 NOTCH（4）和 TP53（3）。与非侵袭性 PA/PitNET 相比，侵袭性 PA/PitNET 中 PARP15、LINC00599 和 ZAP70 的高甲基化更为常见（p<0.05）。侵袭性 PA/PitNET 中 AIP、GNAS 和 PDCD1 的低甲基化水平低于非侵袭性 PA/PitNET（p<0.05）。对于 X 连锁基因，男性侵袭性与非侵袭性 PA/PitNET 中 FLNA、UXT 和 MAGE 家族（MAGEA11、MAGEA1、MAGEC2）基因的甲基化水平更高（p<0.05）。在垂体癌中，与 PitNET 相比，PARP15、LINC00599、MIR193 和 ZAP70 等常染色体基因的甲基化水平较高，而 X 连锁基因的甲基化水平较低。
非侵袭性和侵袭性 PA/PitNET 中涉及细胞增殖/分化、miRNA/LncRNA-转录后调控因子和抗肿瘤治疗靶点的基因的体细胞突变和甲基化水平不同。根据性别不同，甲基化谱也有所不同。结合遗传-表观遗传分析，结合临床、放射和病理数据，可能有助于预测 PA/PitNET 的行为。
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