TY - JOUR
T1 - Deletional, mutational, and methylation analyses of CDKN2 (pI6/MTSI) in primary and merastatic prostate cancer
AU - Jarrard, David F.
AU - Steven Bova, G.
AU - Ewing, Charles M.
AU - Pin, Sokhom S.
AU - Nguyen, Son H.
AU - Baylin, Stephen B.
AU - Cairns, Paul
AU - Sidransky, David
AU - Herman, James G.
AU - Isaacs, William B.
PY - 1997
Y1 - 1997
N2 - The tumor suppressor gene CDKN2 (pI6/MTSI) resides on chromosome 9p21 and encodes a 16 kDa inhibitor of the cyclin-dependent kinases. Inactivation of CDKN2 by hornozygous deletion, point mutation, and recently described aberrant methylation in the 5' promoter region may increase progression through the cell cycle in tumors. In this study, we examine the CDKN2 gene for the presence of inactivating alterations in human prostate cancer. Sequence analysis of cell fines revealed no mutation in LNCaP, PC3, and TSU- PRI and a missense mutation, GAC→TAC (asp to tyr), in exon 2 of the DU145 cell line at codon 76. No mutations were identified in three primary prostate cancers or in seven lymph node metastases. Loss of heterozygosity (LOH) was analyzed by analysis of microsatellite markers in the vicinity of the CDKN2 gene. LOH was detected in 12 (20%) of 60 primary tumors at one or more loci and in 13 (46%) of 28 metastases. Methylation analysis of the CpG-rich promoter region revealed a dense methylation of CDKN2 in cell lines PC3, PPCI, and TSU-PRI, and this was found to correlate with a lack of mRNA expression by reverse transcription-polymerase chain reaction. A demethylating agent, 5-aza-2'-deoxycytidine, induced reexpression when cells were exposed in vitro. DUI45 and LNCaP expressed the CDKN2 transcript and were unmethylated in the promoter region. Three of twenty-four (13%) primary prostate cancers and 1 of 12 metastatic tumors demonstrated promoter methylation. No normal prostate tissues were methylated at the CDKN2 gene promoter. One tumor was found to contain concomitant LOH and promoter methylation indicative of biallelic inactivation. A comprehensive analysis of CDKN2 in prostate cancer reveals that point mutations are infrequent, but gene deletion and methylation combine to inactivate CDKN2 in a subset of tumors. Moreover, alterations in this gene may represent a late event in prostate cancer progression.
AB - The tumor suppressor gene CDKN2 (pI6/MTSI) resides on chromosome 9p21 and encodes a 16 kDa inhibitor of the cyclin-dependent kinases. Inactivation of CDKN2 by hornozygous deletion, point mutation, and recently described aberrant methylation in the 5' promoter region may increase progression through the cell cycle in tumors. In this study, we examine the CDKN2 gene for the presence of inactivating alterations in human prostate cancer. Sequence analysis of cell fines revealed no mutation in LNCaP, PC3, and TSU- PRI and a missense mutation, GAC→TAC (asp to tyr), in exon 2 of the DU145 cell line at codon 76. No mutations were identified in three primary prostate cancers or in seven lymph node metastases. Loss of heterozygosity (LOH) was analyzed by analysis of microsatellite markers in the vicinity of the CDKN2 gene. LOH was detected in 12 (20%) of 60 primary tumors at one or more loci and in 13 (46%) of 28 metastases. Methylation analysis of the CpG-rich promoter region revealed a dense methylation of CDKN2 in cell lines PC3, PPCI, and TSU-PRI, and this was found to correlate with a lack of mRNA expression by reverse transcription-polymerase chain reaction. A demethylating agent, 5-aza-2'-deoxycytidine, induced reexpression when cells were exposed in vitro. DUI45 and LNCaP expressed the CDKN2 transcript and were unmethylated in the promoter region. Three of twenty-four (13%) primary prostate cancers and 1 of 12 metastatic tumors demonstrated promoter methylation. No normal prostate tissues were methylated at the CDKN2 gene promoter. One tumor was found to contain concomitant LOH and promoter methylation indicative of biallelic inactivation. A comprehensive analysis of CDKN2 in prostate cancer reveals that point mutations are infrequent, but gene deletion and methylation combine to inactivate CDKN2 in a subset of tumors. Moreover, alterations in this gene may represent a late event in prostate cancer progression.
UR - http://www.scopus.com/inward/record.url?scp=0343580444&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0343580444&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1098-2264(199706)19:2<90::AID-GCC4>3.0.CO;2-V
DO - 10.1002/(SICI)1098-2264(199706)19:2<90::AID-GCC4>3.0.CO;2-V
M3 - Article
C2 - 9171999
AN - SCOPUS:0343580444
SN - 1045-2257
VL - 19
SP - 90
EP - 96
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
IS - 2
ER -