Endocrine Abstracts

Introduction: Typical and Atypical bronchial carcinoids (TBC and ABC) are rare neuroendocrine neoplasms (NEN). TBC are low grade and well-differentiated NEN often with indolent clinical behavior, slow growth, rare extra-thoracic metastases, and with a long survival following surgical resection. Conversely, ABC have often a worse prognosis with a greater tendency to metastasize and recur. A better understanding of TBC and ABC genetic background would help in evaluating prognosis, especially in advanced BC resistant to treatment.

Aim: Investigate by whole-genome sequencing the mutational profile in TBC vs. ABC using a multigenic panel previously employed in pancreatic NEN.

Materials and methods: Genomic DNA was isolated from 25 TBC and 13 ABCs frozen samples. 11 genes (MEN1, DAXX, ATRX, MUTYH, SETD2, DEPDC5, TSC2, ARID1A, CHECK2, MTOR, PTEN) were sequenced by Next Generation Sequencing (NGS).

Results: TBC more frequently presented alterations vs. ABC in TSC2, ARID1A and DEPDC5 genes (OR 5.4, 3.7 and 3.7, respectively). Specifically, 32% of TBC samples showed alterations in the DUF3384 domain of TSC2 gene, 24% in ARID1A and/or DEPDC5 genes. TSC2, ARID1A and DEPDC5 were altered in 8% of ABC samples, respectively.

Conclusions: The present study suggests that TBC are more frequently mutated in TSC2, ARID1A and DEPDC5 genes as compared to ABC. Interestingly, preliminary studies indicate that TGF-B and mTOR crosstalk might contribute to resistance to everolimus (an mTOR inhibitor) in advanced TBC, which might be explained by altered TSC2 gene (involved in mTOR signalling) in our study. In light of these findings, further studies with larger and balanced groups are needed to confirm these observations and to investigate the clinical significance of these mutations in TBC and ABC, as well as to explore the potential therapeutic implications of targeting TSC2 and other genes identified in our study in TBC and ABC.