Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors

Crona, Joakim; Gustavsson, Tobias; Norlén, Olov; Edfeldt, Katarina; Åkerström, Tobias; Westin, Gunnar; Hellman, Per; Björklund, Peyman; Stålberg, Peter

doi:10.1245/s10434-014-4351-9

Cited by 69 publications

(61 citation statements)

References 28 publications

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“…Cell cycle deregulation may thus be one potential mechanism in SI-NET tumorigenesis. A further study aimed to re-sequence a clinically well-characterized cohort consisting of 362 SI-NET samples from 200 patients for CDKN1B mutations and to investigate possible genotypephenotype correlations (Crona et al 2015). This study confirmed CDKN1B as a potential tumour suppressor gene in SI-NET.…”

Section: Small Intestinal Netmentioning

confidence: 72%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Section: Small Intestinal Netmentioning

confidence: 72%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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“…The genomic landscape of SI-NETs has been investigated with exome coverage in close to 100 tumor samples (136,137). Recurrent mutations were only identified in the CDKN1B gene with a mutation prevalence of 9% of SI-NET patients (136,137,138). Instead, the most frequent genomic alteration is hemizygous deletions affecting chromosome 18q (133,136,137,139).…”

Section: Small Intestinal Netsmentioning

confidence: 99%

“…Whether these are the consequences of independent tumor formation or metastatic spread remain to be settled (144,145). Recent studies highlighted that a subset of SI-NETs show pronounced genetic heterogeneity within and between tumor lesions (136,138). Korpershoek et al (150) determined, by using LOH markers, that there is genetic heterogeneity within different areas of selected PCCs and PGLs.…”

Section: Genetic Heterogeneity and Tumor Evolutionmentioning

confidence: 99%

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Crona

Skogseid

2016

European Journal of Endocrinology

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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

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“…Mutations occurring in CDKN1B are loss-of-function truncating mutations that occur throughout the gene. Mutational status does not appear to correlate with expression of p27 (the protein product of CDKN1B) and has no detectable association with clinical characteristics or survival (4). Given the low frequency of mutations in this putative tumor suppressor gene, and the absence of other obvious pathogenetic genome alterations, we hypothesized that alternative mechanisms such as epigenetic dysregulation are likely to play a role in these tumors (5).…”

Section: Introductionmentioning

confidence: 99%

“…The most frequent genomic event identified in SINETs is loss of heterozygosity (LOH) at chromosome 18, occurring in 60% to 78% of tumors (2,3); more recently, recurrent mutations in the cell cycle regulator CDKN1B (cyclin-dependent kinase inhibitor 1B) have been identified in approximately 8% of tumors in large-scale sequencing studies (3,4). Mutations occurring in CDKN1B are loss-of-function truncating mutations that occur throughout the gene.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

Karpathakis

Dibra

Pipinikas

et al. 2016

Clinical Cancer Research

163

149

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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.

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Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors

Abstract: This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

Cited by 69 publications

References 28 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

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