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Published on: September 8, 2023
Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor
Anna Karpathakis1, Harpreet Dibra2, Chistodoulos Pipinikas2
1University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom.
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.
Insights
Small intestinal neuroendocrine tumors (SINETs) are epigenetically dysregulated, with novel molecular subtypes impacting progression-free survival. This study reveals key drivers beyond mutations in these common small intestine cancers.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Small intestinal neuroendocrine tumors (SINETs) are the most common small intestine malignancy.
- Pathogenic mechanisms of SINETs are poorly understood, with limited known mutations (e.g., CDKN1B in ~8%).
- This highlights the need for alternative mechanisms driving SINET tumorigenesis.
Purpose of the Study:
- To conduct comprehensive genome-wide molecular profiling of SINETs.
- To identify pathogenic drivers of SINET development using integrated genomic, epigenomic, and transcriptomic analyses.
- To establish the largest unbiased molecular dataset for SINETs to date.
Main Methods:
- Integrated molecular analysis of 97 SINETs.
- Whole-exome/targeted sequencing (CDKN1B), DNA methylation array (HumanMethylation450), ChIP-sequencing, copy-number analysis, and gene expression profiling (Whole-Genome DASL).
Main Results:
- SINETs classified into three molecular subtypes with distinct progression-free survival outcomes (p=0.04).
- High recurrence rate of epimutations (up to 85%) identified.
- 21 epigenetically dysregulated genes discovered, including CDX1, CELSR3, FBP1, and GIPR.
Conclusions:
- This study presents the first comprehensive integrated molecular analysis of SINETs.
- SINETs exhibit significant epigenetic dysregulation.
- Novel molecular subtypes impacting progression-free survival were identified, offering new insights into SINET pathogenesis.
