Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.

中文翻译：

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垂体神经内分泌肿瘤的泛基因组分类。

垂体神经内分泌肿瘤 (PitNETs) 很常见，主要有五种组织学亚型：催乳素细胞、生长素细胞和促甲状腺素细胞（POU1F1/PIT1 谱系）；促肾上腺皮质激素（TBX19/TPIT 谱系）；和促性腺激素（NR5A1/SF1 谱系）。我们报告了 PitNETs 的全面泛基因组分类。来自 POU1F1/PIT1 谱系的 PitNETs 显示出弥漫性 DNA 低甲基化的表观遗传特征，具有转座因子表达和染色体不稳定性（GNAS 突变的生长激素除外）。在 TPIT 谱系中，促皮质激素分为三类：具有明显分泌的 USP8 突变型、具有增加的侵袭性和增加的上皮间质转化的 USP8-野生型，以及具有促性腺激素转分化的大型沉默肿瘤。在 GNAS 野生型生长激素（SF1 表达）中也发现了促性腺激素标志物的意外表达，挑战了当前对 SF1/促性腺激素谱系的定义。这种分类提高了我们的理解并影响了 PitNETs 患者的临床分层。