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Frequent alteration of CDKN2 (p16(INK4A)/MTS1) expression in human primary prostate carcinomas
S G Chi1, R W deVere White, J T Muenzer
1Department of Urology, Division of Hematology and Oncology, School of Medicine, University of California, Davis, Sacramento, California 95817, USA.
Abstract:
CDKN2 (p16(INK4A)/MTS1) is found to be mutated in a variety of human tumor types. To explore the involvement of CDKN2 in prostate carcinogenesis, alterations of CDKN2 were examined in 116 human prostate tissues and cell lines and xenografts. Markedly reduced expression of CDKN2 mRNA was found in 43% (26 of 60) of untreated primary carcinomas, whereas no alteration was observed in 10 benign prostatic hyperplasias. In 17 matched sets from individual patients, 41% of cancerous tissues in contrast to 6% of noncancerous tissues expressed low levels of CDKN2 mRNA, supporting the role of CDKN2 as a tumor suppressor in prostate cancer. Alteration of CDKN2 was observed in each prostate tumor cell line, including one with a missense mutation, and in one of three xenograft tumor tissues derived from primary carcinomas. Two cell lines (PC-3 and TSU-Pr1) expressed only CDKN2 E1beta transcripts, indicating that the expression of CDKN2 E1alpha and E1beta are under separate control in the prostate. A high level of CDKN2 expression was related to abnormal RB1 in one primary tumor and in the DU145 cell line, which expressed the mutated CDKN2 allele. Analysis of genomic DNA indicated that altered CDKN2 expression in primary carcinomas of the prostate was more frequently due to down-regulation of transcription (five of seven) than deletion of the gene (two of seven). Additionally, CDKN2 mRNA was induced in nonexpressor cell lines by treatment with 5-aza-2'-deoxycytidine. This study demonstrates that alteration of CDKN2 is one of the most frequent genetic abnormalities in prostate cancer and may contribute to prostate carcinogenesis.
Insights
Alterations in the CDKN2 gene are frequent in prostate cancer, with reduced expression observed in many primary tumors. This suggests CDKN2 acts as a tumor suppressor, potentially contributing to prostate carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The CDKN2 gene, also known as p16(INK4A)/MTS1, is frequently mutated in various human cancers.
- Understanding the role of CDKN2 in prostate cancer development is crucial for identifying potential therapeutic targets.
Purpose of the Study:
- To investigate the alterations and expression patterns of the CDKN2 gene in prostate carcinogenesis.
- To determine the frequency and mechanisms of CDKN2 gene involvement in prostate cancer.
Main Methods:
- Analysis of CDKN2 gene expression (mRNA levels) and alterations in 116 human prostate tissues, cell lines, and xenografts.
- Examination of matched cancerous and non-cancerous tissues from patients.
- Investigation of gene deletion, transcriptional down-regulation, and response to 5-aza-2'-deoxycytidine treatment.
Main Results:
- Reduced CDKN2 mRNA expression was found in 43% of untreated primary prostate carcinomas, but not in benign prostatic hyperplasias.
- Significantly lower CDKN2 mRNA levels were observed in cancerous tissues compared to non-cancerous tissues from the same patients.
- Alterations in CDKN2 were detected in all prostate tumor cell lines and in one xenograft.
- Down-regulation of transcription was a more common mechanism than gene deletion for altered CDKN2 expression in primary tumors.
- CDKN2 mRNA expression could be induced in nonexpressor cell lines by 5-aza-2'-deoxycytidine treatment.
Conclusions:
- Alterations in the CDKN2 gene are among the most frequent genetic abnormalities observed in prostate cancer.
- The findings support a role for CDKN2 as a tumor suppressor in prostate cancer.
- These genetic alterations may contribute to the development of prostate cancer.