Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors

Abstract

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed.Material and methods: 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology.Results: A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, EGFR expression was observed in the investigated tumors in a noteworthy manner. Additionally, MDM2 was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, CDKN2A, was nearly absent in all low-grade tumors. TP53 showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids.Conclusion: Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.

Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single‑center retrospective cohort study and literature review

“…The mutations of KIT, ERBB4 and MET were also reported in these studies, which supported the findings of the present study (27)(28)(29). Notably, one study that used NGS to investigate carcinoids did not provide the original sequencing data and, consequently, the sequencing results were not summarized in Table III; however, it was reported in the study that FGFR1 was highly expressed in carcinoids (39). In addition, Rossi et al (40) also reported that ERBB4 alteration was detected in carcinoids.…”

Molecular alterations of neuroendocrine tumours of the lung

“…Recent studies have investigated carcinoid tumours using non‐ in‐situ techniques. A next‐generation sequencing (NGS) analysis of 14 ‘druggable’ genes in 70 neuroendocrine tumours and mRNA‐expression profiles of 60 matching samples were determined for 13 selected drug targets using NanoString nCounter technology (NanoString Technologies, Inc., Seattle, WA, USA) . In this study, EGFR expression was observed in 87.5% of TC, 100% of AC, 65.3% of LCNEC and 60% of SCLC.…”

“…In addition, MDM2 was expressed strongly in most samples, whereas the expression of its physiological inhibitor, CDKN2A , was almost absent in all TC. TP53 showed a high frequency of variants in high‐grade tumours, but mutations were rare in carcinoids …”

The first pancreatic neuroendocrine tumor in Li-Fraumeni syndrome: a case report

“…Overall, more than half of poorly differentiated GI NECs have somatic TP53 mutations, while 0-11% of moderately and well-differentiated GI NETs harbor the mutation [2,5,10,11]. Similarly, for pulmonary NETs, more than 60% of small cell lung cancer and large cell neuroendocrine carcinoma have TP53 mutations, and 0-11% of well-differentiated grade 1 and 2 pulmonary NETs have been shown to have TP53 mutations [12,13].…”