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Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors
Jessica E Maxwell1, Scott K Sherman1, Guiying Li1
1Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
Abstract:
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.
Insights
CDKN1B gene alterations are confirmed in small bowel neuroendocrine tumors (SBNETs) and pancreatic neuroendocrine tumors (PNETs). These genetic changes in CDKN1B may drive tumor development and suggest new therapeutic strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- CDKN1B, a cell cycle regulator, is implicated as a tumor suppressor in small bowel neuroendocrine tumors (SBNETs).
- Previous studies reported mutation rates of 7.4% for frameshift mutations and 6.7% for hemizygous deletions in SBNET primaries.
Purpose of the Study:
- To validate the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs.
- To investigate the presence of CDKN1B alterations in pancreatic neuroendocrine tumors (PNETs).
Main Methods:
- Genomic DNA extraction from 90 SBNETs and 67 PNETs.
- PCR amplification and sequencing of CDKN1B coding exons.
- Quantitative PCR for CNV analysis and immunohistochemistry for p27 expression.
Main Results:
- In SBNETs, 7.0% of cases showed CDKN1B alterations, including three frameshifts, one missense mutation, and three CNVs.
- The frameshift mutation rate in SBNETs was 3.5%, with a 3.4% rate of hemizygous deletions or duplications.
- PNETs exhibited a 4.8% rate of CDKN1B alterations, including duplications and hemizygous deletions.
Conclusions:
- Alterations in CDKN1B contribute to cell-cycle dysregulation in SBNETs, potentially driving tumor formation.
- These findings highlight CDKN1B as a significant gene in neuroendocrine tumorigenesis.
- Understanding CDKN1B alterations may lead to novel therapeutic approaches for neuroendocrine tumors.
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