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Characterising aggressive pulmonary carcinoids through integrative omics analysis within the lungNENomics Project
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Edité par CCSD ; Lippincott, Williams & Wilkins -
International audience. Introduction Typical and atypical carcinoids are well differentiated lung neuroendocrine tumours (LNETs) that belong to the group of lung neuroendocrine neoplasms, which also include highly aggressive lung neuroendocrine carcinomas (LNECs). Although carcinoids show relatively good prognosis in comparison to carcinomas, metastatic disease and relapse do occur. In a previous study we introduced the concept of molecular groups of carcinoids: A (further separated into A1 and A2) and B, which did not clearly correspond to individual histological types. Additionally, we identified six tumours, termed supra-carcinoids, that displayed genuine carcinoid-like morphology, but had clinical and molecular characteristics of LNECs. In comparison to carcinoid A, overall survival rates were lower for the more aggressive carcinoid B and supra-carcinoid tumours. As yet, little is known about the underlying biology or developmental origins of these two groups of aggressive carcinoids, hampering efforts to identify predictive markers and suitable therapeutic options. Methods To address these questions we aim to perform comprehensive multi-omic molecular, morphological and clinical characterisation of LNETs. We have generated WGS, RNA sequencing, and DNA methylation array data from a new cohort of 205 LNET patients, enriched for the very rare atypical type. These data have been combined with previously published LNET and LNEC data to perform integrative analysis using multi-omics factor analysis (MOFA), resulting in a molecular map of lung neuroendocrine neoplasms for exploration. Subsequently, we applied the Pareto optimum theory over the map to identify specialised tumour profiles resulting from natural selection for cancer tasks. Results Through the integration of multi-omic data with MOFA we obtained five axes (factors) of variation. Visualising the first three factors results in a tetrahedron, with each vertex corresponding to a previously proposed molecular group (Figure 1). Each was characterised by specific clinical and genomic features, as well as cancer-task specialisation, with enrichment for older males with MEN1 alterations and chromosome 11 loss in the more aggressive carcinoid B. Factor 2 separated the high grade LNEC from LNET, and was strongly associated with overall survival and level of neutrophil infiltration. Along Factor 2 are a subset of carcinoids within the LNEC group (supra-carcinoids), whilst others appeared to straddle the carcinoid/carcinoma boundary, suggesting potential progression from an indolent to a more aggressive phenotype through the acquisition of molecular alterations and changes in microenvironment. Conclusions Through this work we have identified molecular and morphological characteristics of aggressive pulmonary carcinoids, which may assist in the clinical management of this rare disease.
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