Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

Autor: Dahmane Oukrif, Mullan Mohmaduvesh, Marinos Pericleous, Matthew Meyerson, Martyn Caplin, Sylvia L. Asa, Joshua M. Francis, Marco Novelli, Dalvinder Mandair, Christodoulos P. Pipinikas, Harpreet Dibra, Tiffany Morris, Matthew H. Kulke, Tim Meyer, Christina Thirlwell, Andrew Feber, Christos Toumpanakis, Stefano Serra, Stephan Beck, Anna Karpathakis, Tu Vinh Luong, Olagunju Ogunbiyi
Rok vydání: 2016
Předmět:
Adult
Male
0301 basic medicine
Cancer Research
DNA Copy Number Variations
DNA Mutational Analysis
Biology
Bioinformatics
Epigenesis
Genetic
Transcriptome
03 medical and health sciences
0302 clinical medicine
Small Intestinal Neuroendocrine Tumor
Intestinal Neoplasms
Intestine
Small
medicine
Cluster Analysis
Humans
Exome
Methylated DNA immunoprecipitation
Neoplasm Metastasis
Exome sequencing
Aged
Neoplasm Staging
Epigenomics
Gene Expression Profiling
Computational Biology
High-Throughput Nucleotide Sequencing
Reproducibility of Results
DNA Methylation
Middle Aged
Prognosis
medicine.disease
Primary tumor
Gene expression profiling
Neuroendocrine Tumors
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Mutation
Cancer research
Female
Chromosomes
Human
Pair 18
Cyclin-Dependent Kinase Inhibitor p27
Zdroj: Clinical Cancer Research. 22:250-258
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-15-0373
Popis: 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.
Databáze: OpenAIRE
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