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Clin Cancer Res. 2016 Jan 1;22(1):250-8. doi: 10.1158/1078-0432.CCR-15-0373. Epub 2015 Jul 13.

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

Author information

1
University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom.
2
University College London, London, United Kingdom.
3
The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
4
The Royal Free Hospital, London, United Kingdom.
5
UHN Princess Margaret Cancer Centre, Toronto, Canada.
6
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
7
University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom. christina.thirlwell@ucl.ac.uk.

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.

PMID:
26169971
DOI:
10.1158/1078-0432.CCR-15-0373
[Indexed for MEDLINE]
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