Different genetic signatures of small‐cell lung cancer characterize anti‐GABABR and anti‐Hu paraneoplastic neurological syndromes
Alberto Vogrig, Antoine Pegat, Macarena Villagrán‐García, Valentin Wucher, Valéry Attignon, Emilie Sohier, Marie Brevet, Veronique Rogemond, Anne‐Laurie Pinto, Sergio Muñiz‐Castrillo, Elise Peter, Melisse Robert, Géraldine Picard, Lucie Hopes, Dimitri Psimaras, Anthony Terra, Corinne Perrin, Dominique Cogne, Severine Tabone‐Eglinger, Séverine Martinez, Delphine Jury, Julie Valantin, Nicolas Gadot, Jessie Auclair‐Perrossier, Alain Viari, Bertrand Dubois, Virginie Desestret, Jérôme Honnorat- Neurology (clinical)
- Neurology
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 (GABABR) antigens. Our aim was to clarify if the genomic and transcriptomic features of SCLC are different in patients with anti‐GABABR or anti‐Hu PNS compared with SCLC without PNS.
Methods
A total of 76 SCLC tumor samples were collected: 34 anti‐Hu, 14 anti‐GABABR, 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.
Results
CNV analysis revealed that patients with anti‐GABABR 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‐GABABR PNS. Pathway analysis revealed that tumors of patients with anti‐GABABR 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.
Interpretation
SCLC genetic and transcriptomic features differentiate anti‐GABABR, anti‐Hu, and non‐PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti‐GABABR PNS.
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