整合甲基化组和转录组特征可扩展垂体肿瘤的分子分类。

Integrating Methylome and Transcriptome Signatures Expands the Molecular Classification of the Pituitary Tumors.

作者信息

Silva-Júnior Rui M Patrício da, Bueno Ana Carolina, Martins Clarissa Silva, Coelli-Lacchini Fernanda, Ozaki Jorge Guilherme Okanobo, Almeida-E-Silva Danillo Cunha de, Marrero-Gutiérrez Junier, Santos Antônio Carlos Dos, Garcia-Peral Carlos, Machado Hélio Rubens, Santos Marcelo Volpon Dos, Elias Paula Lamparelli, Moreira Ayrton C, Colli Leandro M, Vêncio Ricardo Z N, Antonini Sonir R, de Castro Margaret

机构信息

Department of Internal Medicine, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, SP CEP 14049-900, Brazil.

Department of Pediatrics, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, SP CEP 14049-900, Brazil.

出版信息

J Clin Endocrinol Metab. 2023 May 17;108(6):1452-1463. doi: 10.1210/clinem/dgac703.

DOI:10.1210/clinem/dgac703

PMID:36504388

Abstract

OBJECTIVE

To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population.

METHODS

In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo.

RESULTS

Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs).

CONCLUSION

This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

摘要

目的

通过甲基化组和转录组特征在异质种族人群中探索垂体肿瘤。

方法

在这项回顾性横断面研究中，对圣保罗大学里贝朗普雷图医学院77例患者（61%为女性，年龄12 - 72岁）的垂体肿瘤的临床病理特征、甲基化组和转录组进行了评估，这些患者因功能性垂体肿瘤（FPT：生长激素分泌型n = 18，促肾上腺皮质激素分泌型n = 14）和无功能性垂体肿瘤（NFPT，n = 45）而接受随访。

结果

对甲基化组（n = 77）和转录组（n = 77中的65）进行无监督层次聚类分析（UHCA），各自揭示了3个聚类：一个以FPT富集，一个以NFPT富集，第三个以促肾上腺皮质激素分泌型和NFPT富集。每个组学衍生聚类之间的比较分别鉴定出3568个和5994个差异甲基化和表达的基因，它们彼此相关，并与肿瘤临床表现以及2017年和2022年世界卫生组织分类相关。考虑与垂体发育/分化相关的11个转录本的UHCA也支持3个聚类：POU1F1驱动的生长激素细胞腺瘤、TBX19驱动的促肾上腺皮质激素细胞腺瘤和NR5A1驱动的促性腺激素细胞腺瘤，仅有少数例外（NR5A1在少数生长激素分泌型和促肾上腺皮质激素细胞沉默腺瘤中表达；POU1F1在少数促肾上腺皮质激素分泌型腺瘤中表达；TBX19在少数NFPT中表达）。

结论

这个庞大的巴西异质种族队列证实，整合的甲基化组和转录组特征可对FPT和NFPT进行分类，它们与临床表现和肿瘤侵袭性相关。此外，NFPT/促肾上腺皮质激素分泌型腺瘤聚类引发了对肿瘤异质性的关注，支持了2017年和2022年世界卫生组织定义所提出的挑战，即在罕见情况下临床表现与垂体谱系标志物之间的差异。最后，公开我们的数据能够使进一步的研究验证参与垂体肿瘤发病机制和预后的基因/通路。