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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.

SUBMITTER: Walter RF

PROVIDER: S-EPMC5166524 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Walter Robert Fred Henry RF Vollbrecht Claudia C Christoph Daniel D Werner Robert R Schmeller Jan J Flom Elena E Trakada Georgia G Rapti Aggeliki A Adamidis Vasilis V Hohenforst-Schmidt Wolfgang W Kollmeier Jens J Mairinger Thomas T Wohlschlaeger Jeremias J Zarogoulidis Paul P Porpodis Konstantinos K Schmidt Kurt Werner KW Mairinger Fabian Dominik FD

Journal of Cancer 20161025 15

<b>Background</b>: 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. <b>Material and methods</b>: 70 representative tumor specimens ...[more]

PMID: 27994651

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Project description:BackgroundLung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows.MethodsA collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes.ResultsAfter filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM- (P=0.022; P=0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P⩽0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P=0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P=0.020).ConclusionsThe implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response.

Project description:Background: Immunotherapy, especially immune checkpoint inhibition, is one of the most sophisticated approaches in cancer therapy. Immune checkpoint inhibition has already been successfully applied for treatment of non-small cell lung cancer and various other entities. Unfortunately, 60% of the cases show signs of therapy resistance. Additionally, a proportion of cases shows initial insensitivity to immune checkpoint inhibition. We consider a novel escape mechanism in association with deficient proteasomal epitope processing to be one prominent reason for initial insensitivity and therapy resistance. Therefore, we aim to identify mutations in association with these so-called processing escapes, in a highly diverse collective of pulmonary neuroendocrine lung tumors. Materials and Methods: Seventy representative tumor specimens of pulmonary neuroendocrine lung tumors were analyzed retrospectively via immunohistochemical detection of CD4, CD8, CD68, and CD20 as well as programmed cell death protein 1 and programmed cell death 1 ligand 1 for tumor immune infiltration and composition. Afterward, samples were screened for alterations in 48 genes, including 221 known mutational hotspots by massive parallel sequencing using the Illumina TruSeq Amplicon-Cancer Panel. For prediction of proteasomal cleavage probabilities, an R implementation of the machine learning tool NetChop 3.1 was utilized. Results: Immune cell infiltration of different compositions could be found in the majority of tumors. Deficient epitope processing was revealed to be a common event in those with steady distribution across all different subtypes. Despite immune infiltration, no significant antitumor response could be detected. Conclusion: Since it is widely acknowledged that tumors need to avoid the immune system to ensure their survival, processing escapes should already be present during primary tumor development. In line, processing escapes can be found in all tumors, regardless of subtype and mutational burden. Furthermore, there is solid evidence that processing escapes have a negative impact on the antitumor activity of tumor infiltrating immune cells.

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

Publications

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

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