Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology

<b><i>Introduction:</i></b> High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. <b><i>Methods:</i></b> Eleven patients with high-grade (&#x3e;20% Ki-67 and/or &#x3e;10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). <b><i>Results:</i></b> Genomic patterns were heterogeneous ranging from “quiet” to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6–17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (<i>KMT2A</i>, <i>ARID1A</i>, <i>SETD2</i>, <i>SMARCA2</i>, <i>BAP1</i>, <i>PBRM1</i>, <i>KAT6A</i>), DNA repair (<i>MEN1</i>, <i>POLQ</i>, <i>ATR</i>, <i>MLH1</i>, <i>ATM</i>), cell cycle (<i>RB1</i>, <i>TP53</i>, <i>CDKN2A</i>), cell adhesion (<i>LATS2</i>, <i>CTNNB1</i>, <i>GSK3B</i>) and metabolism (<i>VHL</i>). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating “neuroendocrine carcinoma-like” genetic alterations through progression such as <i>TP53/RB1</i> alterations. <b><i>Conclusion:</i></b> These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of <i>TP53</i> and <i>RB1</i> to drive the transformation in more aggressive high-grade tumours.