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. Clin Cancer Res; 22(1); 250–8. ©2015 AACR.

Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma

“…However, in our larger analysis in this study, we found that copy-number loss and promoter methylation could explain the decreased expression of FBP1. FBP1 promoter methylation downregulated FBP1 expression in patients with basal-like breast cancer (7), gastric cancer (32), and small intestinal neuroendocrine tumor (33). Copynumber loss of FBP1 was also observed in ccRCC cases (34).…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Instead, the most frequent genomic alteration is hemizygous deletions affecting chromosome 18q (133,136,137,139). Recent data have shown that SI-NETs can be sub-classified based on tumor methylome into three distinct clusters (140,141). Sub classification of SI-NETs based on gene expression may also provide relevant information (142).…”

Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains

“…However, NETs of the small intestine (SI-NETs) are the most common tumors of this part of the gastrointestinal system [1] and have experienced a dramatic increase in incidence over the past three decades [2] . SI-NETs are tumors with low rates of somatic mutations, as shown in 2 recent studies involving the analysis of 48 and 180 SI-NETs, respectively, by massive parallel sequencing, which revealed a mutation frequency (single nucleotide variants; SNVs) of approximately 0.1 per 10 6 nucleotides. PI3K/Akt/mTOR signaling molecules showed copy number changes in 29% of the analyzed cases.…”

“…SERPINB5 , coding for maspin. In addition, the authors were able to classify SI-NETs in three distinct subgroups, with the Chr18 LOH group being the most favorable and significantly associated with reduced global methylation status [in contrast to no copy number variations (CNVs) and multiple CNVs] [6] . Although these recent reports gave important new insights into the genetic events in SI-NET, not one of the putative tumor suppressors or oncogenic proteins has been studied at the protein level.…”