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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