Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors.
Functional inactivation of the Rb and p53 pathways appears to be a rite of passage for all cancerous cells. However, p53 and Rb alterations are rare events in neuroendocrine gastroenteropancreatic (GEP) tumors. The CDKN2 locus on chromosome 9p21 sits at the nexus of both pathways harboring tumor suppressor genes, which restrain cell growth by affecting the function of pRb and p53. Therefore, we analyzed the implication of their inactivation in 37 primary neuroendocrine GEP tumors and two cell culture models. RT-PCR analysis revealed loss of expression of at least one of the tumor suppressor genes CDKN2A/p16, CDKN2B/p15, and CDKN2D/p14 with distinct genetic profiles, most frequently in nonfunctional pancreatic tumors (57%) and small intestinal carcinoids (44%), and less commonly in insulinomas (30%) and gastrinomas (22%). DNA analysis and methylation-specific PCR attributed loss of expression to either homozygous deletion or 5'CpG island hypermethylation. 5-Aza-2-deoxycytidine treatment reversed CDKN2A/p16 and CDKN2B/p15 silencing with concurrent growth restraint. Thus, tumor suppressor genes localized in the 9p21 gene cluster are specific targets of inactivation in neuroendocrine GEP tumors, and demethylating agents might hold promise for selective therapy.
Lubomierski
N
N
Department of Internal Medicine, Division of Gastroenterology, Philipps-University Marburg, 35033 Marburg, Germany.
Kersting
M
M
Bert
T
T
Muench
K
K
Wulbrand
U
U
Schuermann
M
M
Bartsch
D
D
Simon
B
B
D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002869:Chromosome Aberrations; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D019175:DNA Methylation; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D019942:Genes, p16 / Q000235:genetics; D006801:Humans; D005810:Multigene Family / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; C493974:CDKN2D protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D025521:Tumor Suppressor Proteins