Non-recurrent mutations and copy number changes predominate pituitary adenoma genomes.

IF 5.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Dipika R Mohan, Ticiana Paes, Jacobo Buelvas Mebarak, David M Meredith, Beatriz Soares, Victor Vaz, Rona S Carroll, Ursula B Kaiser, Timothy R Smith, Wenya L Bi, Antonio M Lerario, Ana Paula Abreu
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引用次数: 0

Abstract

Objective: Pituitary adenomas (PAs) are common neoplasms. Our current understanding of the molecular basis of PA formation is incomplete. Routine implementation of targeted genomics has enabled the discovery of rare, potentially clinically actionable events.

Methods: We used a cancer-focused gene panel to sequence a cohort of 171 PAs from patients who underwent surgery at Brigham and Women's Hospital from 2012 to 2020.

Results: We identified known genetic variants enriched in specific PA subtypes: GNAS (somatotroph) and USP8 (Cushing's disease). Total mutational burden did not vary across adenoma subtypes; most adenomas possessed a few non-recurrent mutations in various established oncogenes and tumor suppressors. In contrast, the burden of copy number alterations varied widely across adenoma subtypes and was associated with higher MIB1 labeling index. We identified frequent deletions spanning MEN1 in prolactinomas and silent corticotroph adenomas, and subtype-specific copy number changes including 16p, 16q alterations in somatotroph adenomas without GNAS mutations. Within the corticotroph lineage, adenomas leading to Cushing's disease had few copy number alterations while silent corticotroph adenomas had numerous.

Conclusions: This study highlights a role for individualized genetic events in PA formation and suggests that divergent patterns of genomic instability may facilitate tumorigenesis even within the same lineage. Taken together, we demonstrate how gene panels may illuminate novel biology in endocrine tumors.

非复发性突变和拷贝数变化是垂体腺瘤基因组的主要特征。
目的:垂体腺瘤是一种常见的肿瘤。我们目前对PA形成的分子基础的了解是不完整的。靶向基因组学的常规实施使得发现罕见的、潜在的临床可操作事件成为可能。方法:我们使用以癌症为重点的基因面板对2012年至2020年在布里格姆妇女医院接受手术的患者的171个PAs进行测序。结果:我们确定了已知的遗传变异富集于特定PA亚型:GNAS(生长缺陷)和USP8(库欣病)。腺瘤亚型的总突变负荷没有变化;大多数腺瘤在各种已建立的癌基因和肿瘤抑制因子中具有一些非复发性突变。相反,拷贝数改变的负担在腺瘤亚型之间差异很大,并且与较高的MIB1标记指数相关。我们在泌乳素瘤和无症状的促皮质腺瘤中发现了MEN1的频繁缺失,在没有GNAS突变的生长腺瘤中发现了包括16p、16q改变在内的亚型特异性拷贝数变化。在促皮质性腺瘤谱系中,导致库欣病的腺瘤很少有拷贝数改变,而无症状的促皮质性腺瘤有大量拷贝数改变。结论:这项研究强调了个体化遗传事件在PA形成中的作用,并表明即使在同一谱系中,不同的基因组不稳定性模式也可能促进肿瘤的发生。综上所述,我们展示了基因面板如何阐明内分泌肿瘤中的新生物学。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
European Journal of Endocrinology
European Journal of Endocrinology 医学-内分泌学与代谢
CiteScore
9.80
自引率
3.40%
发文量
354
审稿时长
1 months
期刊介绍: European Journal of Endocrinology is the official journal of the European Society of Endocrinology. Its predecessor journal is Acta Endocrinologica. The journal publishes high-quality original clinical and translational research papers and reviews in paediatric and adult endocrinology, as well as clinical practice guidelines, position statements and debates. Case reports will only be considered if they represent exceptional insights or advances in clinical endocrinology. Topics covered include, but are not limited to, Adrenal and Steroid, Bone and Mineral Metabolism, Hormones and Cancer, Pituitary and Hypothalamus, Thyroid and Reproduction. In the field of Diabetes, Obesity and Metabolism we welcome manuscripts addressing endocrine mechanisms of disease and its complications, management of obesity/diabetes in the context of other endocrine conditions, or aspects of complex disease management. Reports may encompass natural history studies, mechanistic studies, or clinical trials. Equal consideration is given to all manuscripts in English from any country.
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