小细胞肺癌（SCLC）是最常与原发性神经系统综合征（PNS）相关的肿瘤，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。我们的目标是澄清在具有抗-GABAB R或抗-Hu PNS的患者中，SCLC的基因组和转录组特征是否与无PNS的SCLC不同。共收集了76个SCLC肿瘤样本：34个抗-Hu，14个抗-GABAB R，以及28个无PNS的SCLC。该研究分为四个步骤：（i）病理确诊；（ii）使用包括自身抗体靶向基因ELAVL1-4、GABBR1-2、KCTD16在内的98个基因面板进行下一代测序；（iii）全基因组拷贝数变异（CNV）分析；（iv）全转录组RNA测序。CNV分析显示，具有抗-GABAB R PNS的患者通常在第5q染色体上发生增益，其中包含KCTD16基因，而抗-Hu和对照组患者则常发生缺失。没有观察到与任何癌神经元基因相关的突变数目显著不同。相反，SCLC的转录组特征不同，并且不同表达的基因使样本能够有效地聚类为三组，反映了基于抗体的分类，其中KCTD16在抗-GABAB R PNS中表达上调。通路分析显示，患有抗-GABAB R脑炎的肿瘤富集了B细胞标志物，而抗-Hu患者的肿瘤则过表达了T细胞和IFN-γ相关的标志物。SCLC的遗传和转录组特征区分了抗-GABAB R、抗-Hu和非PNS肿瘤。KCTD16的作用似乎在抗-GABAB R PNS的肿瘤免疫耐受性破裂中起到关键作用。本文受版权保护，版权所有。

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 (GABAB R) antigens. Our aim was to clarify if the genomic and transcriptomic features of SCLC are different in patients with anti-GABAB R or anti-Hu PNS compared with SCLC without PNS.A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABAB R, and 28 SCLC without PNS. The study consisted of four steps: (i) pathological confirmation; (ii) Next Generation Sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, KCTD16; (iii) genome-wide Copy Number Variation (CNV); (iv) whole-transcriptome RNA sequencing.CNV analysis revealed that patients with anti-GABAB R PNS have commonly a gain in chromosome 5q, which contains KCTD16, while anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, transcriptomic profile of SCLC was different and the differentially expressed genes permitted to effectively cluster the samples into three groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABAB R PNS. Pathway analysis revealed that tumors of patients with anti-GABAB R encephalitis were enriched in B cell signatures, as opposed to those of patients with anti-Hu in which T cell and IFN-γ-related signatures were overexpressed.SCLC genetic and transcriptomic features differentiate anti-GABAB R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABAB R PNS. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.