Further evidence of an evolutionary continuum from a subset of lung carcinoids to aggressive neuroendocrine tumors

Author:

Pelosi Giuseppe1,Melocchi Valentina2ORCID,Dama Elisa,Hofman Paul,De Luca Marco,Albini Adriana,Gemelli Maria,Ricotta Riccardo,Papotti Mauro3,Rosa Stefano La,Uccella Silvia,Harari Sergio,Asiedu Michael,Wigle Dennis,Bianchi Fabrizio4ORCID

Affiliation:

1. University of Milan

2. Institute for Stem-cell Biology, Regenerative Medicine and Innovative Therapies

3. University of Turin

4. Fondazione IRCCS Casa Sollievo della Sofferenza

Abstract

Abstract Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas. An eight-gene signature with copy number variations (CNVs) in neuroendocrine neoplasms (NENs), namely MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53, was used to classify an independent cohort of 54 surgically resectable tumors [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 small cell lung carcinomas (SCLC)], for which transcriptome and mutation data were available. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions and T>C/C>T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high- plasticity cell state and immune system exhaustion. Similar results were also confirmed in an independent validation set of 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC). We herein propose an unexpected shifting to the current pathogenesis paradigm, suggesting that some NECs could secondarily originate from a subset of genomically transformed carcinoids prone to epigenetic mechanism-driven progression.

Publisher

Research Square Platform LLC

Reference52 articles.

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