Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Fernández-Cuesta, Lynnette; Peifer, Martin; Lü, Xin; Sun, Ruping; Ozretić, Luka; Seidel, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M.; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund‐Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin; Russell, Prudence A.; Wainer, Zoe; Solomon, Benjamin; Field, John K.; Hyde, R. Katherine; Davies, Michael; Heukamp, Lukas C.; Petersen, Iver; Perner, Sven; Lovly, Christine M.; Cappuzzo, Federico; Travis, William D.; Wolf, Jürgen; Vingron, Martin; Brambilla, Élisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K.

doi:10.1038/ncomms4518

Cited by 262 publications

(284 citation statements)

References 35 publications

(54 reference statements)

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“…The high prevalence of mutations in chromatin remodelling genes suggests that these mutations are crucial to drive tumorigenesis in a precisely defined spectrum of required cellular pathways (Fernandez-Cuesta et al 2014). Previous studies already reported impairment in specific histone 4 modification levels.…”

Section: Pulmonary Netmentioning

confidence: 99%

“…Mutations of PTEN were found in 7.3% of PanNET and more recently mutations in TSC2, 8.8%; PIK3CA, 1.4% were also described (Perren et al 2000. TP53 mutations are rare in PanNET Jiao et al 2011, Cao et al 2013, Francis et al 2013, Cancer Genome Atlas Research 2014, Fernandez-Cuesta et al 2014, Cromer et al 2015, Lichtenauer et al 2015, Witkiewicz et al 2015, Scarpa et al 2017.…”

Section: Cellmentioning

confidence: 99%

“…In 2014, the whole exome of 69 pulmonary carcinoids was sequenced, revealing the most frequently mutated genes, in addition to MEN1, in this malignancy (Fernandez-Cuesta et al 2014) (Figs 2 and 3). All mutations were found in genes acting in chromatin remodelling pathways.…”

Section: Chromatinmentioning

confidence: 99%

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Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

111

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Section: Pulmonary Netmentioning

confidence: 99%

Section: Cellmentioning

confidence: 99%

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Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

111

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show abstract

“…Epigenetic dysregulation is known to play a key role in other NET development, including tumors of pancreatic and bronchial origin (8,9). Integrated molecular profiling based on methylation analysis has recently been shown to identify clinically distinct subgroups of lung carcinomas, including a neuroendocrine-specific "epitype" (10).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

Karpathakis

Dibra

Pipinikas

et al. 2016

Clinical Cancer Research

165

149

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Purpose: Small intestinal neuroendocrine tumors (SINET) are the commonest malignancy of the small intestine; however, underlying pathogenic mechanisms remain poorly characterized. Whole-genome and -exome sequencing has demonstrated that SINETs are mutationally quiet, with the most frequent known mutation in the cyclin-dependent kinase inhibitor 1B gene (CDKN1B) occurring in only ∼8% of tumors, suggesting that alternative mechanisms may drive tumorigenesis. The aim of this study is to perform genome-wide molecular profiling of SINETs in order to identify pathogenic drivers based on molecular profiling. This study represents the largest unbiased integrated genomic, epigenomic, and transcriptomic analysis undertaken in this tumor type. Experimental Design: Here, we present data from integrated molecular analysis of SINETs (n = 97), including whole-exome or targeted CDKN1B sequencing (n = 29), HumanMethylation450 BeadChip (Illumina) array profiling (n = 69), methylated DNA immunoprecipitation sequencing (n = 16), copy-number variance analysis (n = 47), and Whole-Genome DASL (Illumina) expression array profiling (n = 43). Results: Based on molecular profiling, SINETs can be classified into three groups, which demonstrate significantly different progression-free survival after resection of primary tumor (not reached at 10 years vs. 56 months vs. 21 months, P = 0.04). Epimutations were found at a recurrence rate of up to 85%, and 21 epigenetically dysregulated genes were identified, including CDX1 (86%), CELSR3 (84%), FBP1 (84%), and GIPR (74%). Conclusions: This is the first comprehensive integrated molecular analysis of SINETs. We have demonstrated that these tumors are highly epigenetically dysregulated. Furthermore, we have identified novel molecular subtypes with significant impact on progression-free survival. Clin Cancer Res; 22(1); 250–8. ©2015 AACR.

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“…The libraries were then sequenced with a 2 Â 100 bp paired-end protocol to a minimum mean coverage of 30Â. Data were processed and analyzed as described previously (16,17). All data have been deposited at the European Genome-phenome Archive under the accession code EGAS00001002491.…”

Section: Viability Assays and Compound Activity Predictionmentioning

confidence: 99%

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Malchers

Ercanoglu

Schütte

et al. 2017

Clinical Cancer Research

Self Cite

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Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.

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Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Cited by 262 publications

References 35 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

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