Abstract 5355: Whole genome landscape of small cell lung carcinoma and large cell neuroendocrine carcinoma of the lung

Abstract Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are the most deadly forms of lung cancer. The advent of numerous molecular targeted therapeutics, including immune checkpoint inhibitors, has improved outcomes in non-small cell lung cancer. However, the prognosis for SCLC and LCNEC has shown slight improvement, and the development of novel therapeutics is craved. In addition, because SCLC frequently presents at advanced stages and resected samples are scarce, large-scale genomic analysis has rarely been performed. In particular, while molecular biological classification based on neuroendocrine markers has been proposed so far for SCLC, no classification has been fully established for LCNEC. To refine the classification and to identify vulnerabilities of SCLC and LCNEC, we performed comprehensive multi-omic analyses on 154 samples (107 SCLC and 47 LCNEC) using whole-genome sequencing with both short-read and long-read sequencers, RNA sequencing, and spatial transcriptomics. Integrated transcriptome clustering of SCLC and LCNEC allowed us to classify our cases into three clusters. Each cluster was characterized by distinct molecular features, with distinct profiles of expression patterns, mutations, structural variations, and copy number alterations. We also identified novel driver mutations and recurrent structural variations that were not previously reported. Importantly, we have successfully identified several gene mutations and structural abnormalities which may be functionally significant. Gene X, which we detected as a novel driver gene, is presumed to function as a tumor suppressor gene, and increased TMB was observed in cases with Gene X mutations, regardless of MSI status. In addition, Splicing Factor Y, identified as a novel recurrent structural variation, is a gene that functions as a splicing regulator, and these structural variations affect alternative splicing of genes related to cell morphology, suggesting that they may affect the phenotype of these cancers. Analysis of structural variation using long-read sequencing identified structural variations that could not be detected by short-read sequencing. In addition, spatial transcriptomics elucidated the differences in the tumor microenvironment between SCLC and LCNEC or among the molecular biological classifications. The findings of novel technology-based analyses suggest a new therapeutic strategy for SCLC and LCNEC. Citation Format: Hisashi Hashimoto, Yosuke Tanaka, Jun Takahashi, Toshihide Ueno, Shinya Kojima, Kouya Shiraishi, Takashi Kohno, Yuichi Shiraishi, Yasushi Yatabe, Takeshi Kaneko, Hiroyuki Mano. Whole genome landscape of small cell lung carcinoma and large cell neuroendocrine carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5355.