Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.
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ABSTRACT:
SUBMITTER: Francis JM
PROVIDER: S-EPMC4239432 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.
Francis Joshua M JM Kiezun Adam A Ramos Alex H AH Serra Stefano S Pedamallu Chandra Sekhar CS Qian Zhi Rong ZR Banck Michaela S MS Kanwar Rahul R Kulkarni Amit A AA Karpathakis Anna A Manzo Veronica V Contractor Tanupriya T Philips Juliet J Nickerson Elizabeth E Pho Nam N Hooshmand Susanne M SM Brais Lauren K LK Lawrence Michael S MS Pugh Trevor T McKenna Aaron A Sivachenko Andrey A Cibulskis Kristian K Carter Scott L SL Ojesina Akinyemi I AI Freeman Samuel S Jones Robert T RT Voet Douglas D Saksena Gordon G Auclair Daniel D Onofrio Robert R Shefler Erica E Sougnez Carrie C Grimsby Jonna J Green Lisa L Lennon Niall N Meyer Tim T Caplin Martyn M Chung Daniel C DC Beutler Andreas S AS Ogino Shuji S Thirlwell Christina C Shivdasani Ramesh R Asa Sylvia L SL Harris Chris R CR Getz Gad G Kulke Matthew M Meyerson Matthew M
Nature genetics 20131103 12
The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 ...[more]
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Project description:CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities.
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| phs000579.v1.p1 | EGA
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Project description:Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.
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Project description:BackgroundCurrent diagnostic and prognostic blood-based biomarkers for neuroendocrine tumors are limited. MiRNAs have tumor-specific expression patterns, are relatively stable, and can be measured in patient blood specimens. We performed a multi-stage study to identify and validate characteristic circulating miRNAs in patients with metastatic small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival.MethodsUsing a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with metastatic small intestine NET and 40 controls, and then validated this panel in a second, large cohort of 120 patients with metastatic small intestine NET and 120 independent controls.ResultsmiRNA profiling of 19 matched small intestine neuroendocrine tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p<0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. We confirmed that high circulating levels of miR-22-3p (p<0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p=0.027) were associated with the presence of metastatic small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers was highly prognostic for survival (HR 0.47, 95% CI 0.27-0.82).ConclusionsOur study suggests that elevated circulating levels of miR-21-5p and miR-22-3p and low levels of miR-150-5p are characteristic in patients with metastatic small intestine neuroendocrine tumors, and further suggests that levels of these miRNAs are associated with overall survival. These observations provide the basis for further validation studies, as well as studies to assess the biological function of these miRNAs in small intestine neuroendocrine tumors.
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Project description:Small intestine neuroendocrine tumors (SI-NETs) represent the most common histotype among small intestine neoplasms, and metastatic disease is usually present at diagnosis. A retrospective series of 52 sporadic primary surgically resected SI-NETs, which were metastatic at diagnosis, was analyzed by high-coverage target sequencing (HCTS) for the mutational status of 57 genes and copy number status of 40 genes selected from recently published genome sequencing data. Seven genes were found to be recurrently mutated: CDKN1B (9.6%), APC and CDKN2C (each 7.7%), BRAF, KRAS, PIK3CA, and TP53 (each 3.8%). Copy number analysis showed frequent allelic loss of 4 genes located on chromosome 18 (BCL2, CDH19, DCC, and SMAD4) in 23/52 (44.2%) and losses on chromosomes 11 (38%) and 16 (15%). Other recurrent copy number variations were gains for genes located on chromosomes 4 (31%), 5 (27%), 14 (36%), and 20 (20%). Univariate survival analysis showed that SRC gene copy number gains were associated with a poorer prognosis (p = 0.047). Recurrent copy number variations are important events in SI-NET and SRC may represent a novel prognostic biomarker for this tumor type.
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