Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABABR and Anti-Hu Paraneoplastic Neurological Syndromes

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2023-08-28 DOI:10.1002/ana.26784

Alberto Vogrig MD, PhD, Antoine Pegat MD, Macarena Villagrán-García MD, Valentin Wucher PhD, Valéry Attignon PhD, Emilie Sohier PhD, Marie Brevet MD, PhD, Veronique Rogemond PhD, Anne-Laurie Pinto MSc, Sergio Muñiz-Castrillo MD, PhD, Elise Peter MD, Melisse Robert PhD, Géraldine Picard MSc, Lucie Hopes MD, Dimitri Psimaras MD, Anthony Terra, Corinne Perrin PhD, Dominique Cogne, Severine Tabone-Eglinger PharmD, PhD, Séverine Martinez, Delphine Jury, Julie Valantin, Nicolas Gadot, Jessie Auclair-Perrossier, Alain Viari PhD, Bertrand Dubois PhD, Virginie Desestret MD, PhD, Jérôme Honnorat MD, PhD

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引用次数: 1

Abstract

Objective

Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABA_BR) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABA_BR or anti-Hu PNS compared with SCLC without PNS.

Methods

A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABA_BR, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing.

Results

CNV analysis revealed that patients with anti-GABA_BR PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABA_BR PNS. Pathway analysis revealed that tumors of patients with anti-GABA_BR encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed.

Interpretation

SCLC genetic and transcriptomic features differentiate anti-GABA_BR, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABA_BR PNS. ANN NEUROL 2023;94:1102–1115

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小细胞肺癌的不同遗传特征表征抗gabab R和抗hu副肿瘤神经综合征

目的：癌症（SCLC）是最常见的与副肿瘤性神经综合征（PNS）相关的恶性肿瘤，可引发针对细胞内（Hu）或神经元表面（GABAB R）抗原的不同抗体反应。我们的目的是阐明抗GABAB R或抗Hu PNS患者的SCLC的基因组和转录组学特征与没有PNS的SCLC相比是否不同。该研究包括4个步骤：（1）病理证实；（2）使用一组98个基因的下一代测序，包括编码靶向ELAVL1-4、GABBR1-2和KCTD16的自身抗体的基因；（3）全基因组拷贝数变异；和（4）全转录组RNA测序。结果：CNV分析显示，抗GABAB R PNS患者通常在含有KCTD16的5q染色体上有增加，而抗Hu和对照患者通常有丢失。没有观察到与任何肿瘤神经基因相关的显著不同数量的突变。相反，SCLC的转录组学特征不同，差异表达的基因允许将样本有效地分为3组，反映了基于抗体的分类，其中抗GABAB R PNS特异性的KCTD16过表达。通路分析显示，抗GABAB-R脑炎患者的肿瘤富含B细胞信号，而抗Hu患者的肿瘤中T细胞和干扰素-γ相关信号过表达。解释：SCLC的遗传和转录组学特征区分抗GABAB R、抗Hu和非PNS肿瘤。KCTD16的作用似乎在抗GABAB R PNS的肿瘤免疫耐受破坏中起关键作用。ANN NEUROL 2023。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.