Different Genetic Signatures of Small‐Cell Lung Cancer Characterize <scp>Anti‐GABA<sub>B</sub>R</scp> and <scp>Anti‐Hu</scp> Paraneoplastic Neurological Syndromes
Alberto Vogrig, Antoine Pégat, Macarena Villagrán‐García, Valentin Wucher, Valéry Attignon, Emilie Sohier, Marie Brevet, Véronique Rogemond, Anne‐Laurie Pinto, Sergio Muñiz‐Castrillo, Elise Peter, M. Casellas Robert, Géraldine Picard, Lucie Hopes, Dimitri Psimaras, Anthony Terra, Corinne Perrin, Dominique Cogne, Séverine Tabone‐Eglinger, Séverine Martinez, Delphine Jury, Julie Valantin, Nicolas Gadot, Jessie Auclair‐Perrossier, Alain Viari, Bertrand Dubois, Virginie Desestret, Jérôme Honnorat
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 B R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti‐GABA B R 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 B R, 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 B R 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 B R PNS. Pathway analysis revealed that tumors of patients with anti‐GABA B R 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 B R, anti‐Hu, and non‐PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti‐GABA B R PNS. ANN NEUROL 2023;94:1102–1115