In:
Neuroendocrinology, S. Karger AG, Vol. 111, No. 1-2 ( 2021), p. 158-169
Abstract:
〈 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.
Type of Medium:
Online Resource
ISSN:
0028-3835
,
1423-0194
Language:
English
Publisher:
S. Karger AG
Publication Date:
2021
detail.hit.zdb_id:
1483028-0
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