Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.


中文翻译：

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垂体肿瘤：发病机制和临床行为的遗传和分子因素

垂体神经内分泌肿瘤（PitNETs）是最常见的颅内肿瘤。虽然通常是良性的，但它们可以表现出临床侵袭性过程，具有局部侵袭、复发和对药物治疗的抵抗力。目前还没有普遍接受的攻击性生物标志物，预测 PitNETs 的临床行为仍然是一个挑战。在极少数情况下，特定基因中种系突变的存在易导致 PitNETs 形成，作为综合征疾病或家族性孤立垂体腺瘤 (FIPA) 的一部分，并与更具侵袭性、侵袭性和耐药性肿瘤相关联。绝大多数案例以零星的 PitNET 为代表。刺激性 G 蛋白基因 (gsp) 的  亚基和泛素特异性蛋白酶 8 (USP8) 基因中的体细胞突变已分别被认为是散发 GH 和 ACTH 分泌的 PitNETs 的致病因素，与更糟的情况无关临床表型。已发现其他分子因素显着影响 PitNETs 药物反应性和侵入性行为。这些分子是细胞骨架和/或支架蛋白，其改变会阻止生长抑素和多巴胺受体、药物治疗靶点的正常功能，或促进肿瘤细胞侵入周围组织的能力。本综述的目的是概述可能有助于确定 PitNETs 临床行为的遗传和分子改变。