title: Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors.
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.
authors.affiliation: Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Maxwell
authors.affiliation: Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Sherman
authors.affiliation: Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Guiying
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Choi
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellizzi
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Dorisio
authors.affiliation: Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: james-howe@uiowa.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
keywords: CDKN1B; Neuroendocrine tumor; frameshift mutation; p27; pancreatic neuroendocrine tumor; small bowel neuroendocrine tumor