Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-05-17 DOI:10.1007/s00401-024-02736-8
Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar
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Abstract

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10−10 and p = 8.5 × 10−9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10−4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10−8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

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全基因组杂合性缺失可预测垂体神经内分泌肿瘤的侵袭性和难治性行为
垂体神经内分泌肿瘤(PitNET)具有侵袭性和难治性,是一种罕见的亚型肿瘤,在手术、常规药物治疗和初始放射治疗后仍有进展,其特点是持续生长和/或转移扩散。对两组PitNET患者进行了测序:一组是在手术前同意测序的前瞻性患者(66人),另一组是由侵袭性/高风险PitNET组成的回顾性患者(26人)。与良性肿瘤相比,侵袭性、难治性PitNET的突变负荷和杂合性缺失(LOH)比例更高(p = 1.3 × 10-10 和 p = 8.5 × 10-9)。在皮质营养细胞系中,12条特定染色体的复发性染色体LOH的特征模式与难治性相关(14例难治性PitNET中的11例与14例良性皮质营养细胞PitNET中的1例相关,p = 1.7 × 10-4)。在整个队列中,TP53突变的肿瘤中发现的LOH比例较高(p = 3.3 × 10-8)。机器学习方法发现,杂合性缺失是最具侵袭性、难治性行为的预测变量,其准确率为0.88(95% CI:0.70-0.96),高于最常见的基因水平改变TP53。具有侵袭性、难治性的PitNET因广泛的染色体LOH而具有显著的非整倍体特征,这在皮质营养瘤中最为突出。这种 LOH 预测难治性的准确率很高,是这一定义不清的 PitNET 类别的新型生物标记物。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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