Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor.

Abstract

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.

• Authors: Anna Karpathakis, Harpreet Dibra, Chistodoulos Pipinikas, Andrew Feber, Tiffany Morris, Joshua Francis, Dahmane Oukrif, Dalvinder Mandair, Marinos Pericleous, Mullan Mohmaduvesh, Stefano Serra, Olagunju Ogunbiyi, Marco Novelli, TuVinh Luong, Sylvia L Asa, Matthew Kulke, Christos Toumpanakis, Tim Meyer, Martyn Caplin, Matthew Meyerson, Stephan Beck, Christina Thirlwell
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 1 Pg. 250-8 (Jan 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26169971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p27

Topics

• Adult
• Aged
• Chromosomes, Human, Pair 18
• Cluster Analysis
• Computational Biology (methods)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics)
• DNA Copy Number Variations
• DNA Methylation
• DNA Mutational Analysis
• Epigenesis, Genetic
• Exome
• Female
• Gene Expression Profiling
• High-Throughput Nucleotide Sequencing
• Humans
• Intestinal Neoplasms (diagnosis, genetics, mortality)
• Intestine, Small (metabolism, pathology)
• Male
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Neoplasm Staging
• Neuroendocrine Tumors (diagnosis, genetics, mortality)
• Prognosis
• Reproducibility of Results