Pan-Lung Cancer: Integrative Genomic and Transcriptomic Analysis Suggest Novel Therapeutic Approach

Background: The World Health Organization (WHO) identifies six major histotypes of Lung Neoplasms dividing them according to two main, pure or combined, lineages: neuroendocrine – typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer (SCLC), and non-neuroendocrine – adenocarcinoma (ADC), squamous cell carcinoma (SQC). High-throughput molecular analysis, on a histologically re-evaluated large multicenter series of lung cancers, may be able to provide a more personalized characterization beyond histopathology and develop patient-tailored therapeutic approaches. Design: Six-hundred patients with primary neuroendocrine lung neoplasms were retrieved from 5 Italian Centers, creating a retrospective cohort spanning 40 years (1978-2019), with follow up information. Pathological central revision on surgical specimens, both in terms of morphology and immunohistochemical features, enabled reclassification according to WHO 2021 criteria. Specific WHO categories were deeply characterized by means of wide genomic (409 genes) and transcriptomic (20.815 genes) analyses. Results: Overall, 100 non-neuroendocrine lung neoplasms (40 ADC, 60 SQC), 114 lung neuroendocrine tumors (23 TC, 25 AC, 43 LCNEC, 23 SCLC) and 54 combined-lung tumors (41 co-LCNECs and 13 co-SCLCs) were identified as suitable for genomic and expression NGS analysis. Genomic screening of pure tumours (n=214) showed highly specific genomic alterations for each histotype. Transcriptomic analysis identified two molecular subgroups in each pure histotype, except for SQCs. In more details: two molecular clusters of ADCs were identified, linked both to different outcomes and to the association with the PD-1 blockade pathway, while an SCLC ATR positive and SCLC ATR negative were detected, highlighting new therapeutic possibilities. Deconvolution analysis also divided lung cancers in two major groups: “cold” and “hot” showing LCNECs as potential candidates for immunotherapy. Molecular characterization of combined-lung tumours identified potentially targetable alterations while transcriptomic analysis showed at least 3 distinct and standalone profiles compared to pure histotypes. Conclusions: Our study detailed the molecular landscape of major histotypes of lung neoplasms, highlighting differences and links between various histotypes, and providing indications for a better molecular stratification for the purpose of an increasingly personalized therapeutic management