Abstract:Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on ch… Show more
“…While some common genetic alterations have been identi®ed during prostate cancer progression (Isaacs et al, 1995) and a susceptibility gene for prostate cancer has recently been identi®ed (Smith et al, 1996), the molecular events leading to prostate cancer development are not well de®ned. Initiation of cancer involves multiple genetic events characterized by chromosomal translocations, deletions, ampli®cations and point mutations of critical genes (Knudson, 1986).…”
Glutathione-S-Transferases (GSTs) comprise a family of isoenzymes that provide protection to mammalian cells against electrophilic metabolites of carcinogens and reactive oxygen species. Previous studies have shown that the CpG-rich promoter region of the p-class gene GSTP1 is methylated at single restriction sites in the majority of prostate cancers. In order to understand the nature of abnormal methylation of the GSTP1 gene in prostate cancer we undertook a detailed analysis of methylation at 131 CpG sites spanning the promoter and body of the gene. Our results show that DNA methylation is not con®ned to speci®c CpG sites in the promoter region of the GSTP1 gene but is extensive throughout the CpG island in prostate cancer cells. Furthermore we found that both alleles are abnormally methylated in this region. In normal prostate tissue, the entire CpG island was unmethylated, but extensive methylation was found outside the island in the body of the gene. Loss of GSTP1 expression correlated with DNA methylation of the CpG island in both prostate cancer cell lines and cancer tissues whereas methylation outside the CpG island in normal prostate tissue appeared to have no e ect on gene expression.
“…While some common genetic alterations have been identi®ed during prostate cancer progression (Isaacs et al, 1995) and a susceptibility gene for prostate cancer has recently been identi®ed (Smith et al, 1996), the molecular events leading to prostate cancer development are not well de®ned. Initiation of cancer involves multiple genetic events characterized by chromosomal translocations, deletions, ampli®cations and point mutations of critical genes (Knudson, 1986).…”
Glutathione-S-Transferases (GSTs) comprise a family of isoenzymes that provide protection to mammalian cells against electrophilic metabolites of carcinogens and reactive oxygen species. Previous studies have shown that the CpG-rich promoter region of the p-class gene GSTP1 is methylated at single restriction sites in the majority of prostate cancers. In order to understand the nature of abnormal methylation of the GSTP1 gene in prostate cancer we undertook a detailed analysis of methylation at 131 CpG sites spanning the promoter and body of the gene. Our results show that DNA methylation is not con®ned to speci®c CpG sites in the promoter region of the GSTP1 gene but is extensive throughout the CpG island in prostate cancer cells. Furthermore we found that both alleles are abnormally methylated in this region. In normal prostate tissue, the entire CpG island was unmethylated, but extensive methylation was found outside the island in the body of the gene. Loss of GSTP1 expression correlated with DNA methylation of the CpG island in both prostate cancer cell lines and cancer tissues whereas methylation outside the CpG island in normal prostate tissue appeared to have no e ect on gene expression.
“…Its tumour suppressor potential has been postulated since the introduction of truncated RNase L protein in murine cells abolished the antiproliferative effect of interferon (Hassel et al, 1993). The RNASEL gene locus at 1q25 (HPC1) has been implicated in prostate cancer susceptibility as a result of the first genome wide linkage scan, which included 91 hereditary prostate cancer pedigrees from North America and Sweden (Smith et al, 1996). Linkage to HPC1 seemed to be stronger in families with early-onset disease.…”
To date, germline mutations have been found in three candidate genes for hereditary prostate cancer: ELAC2 at 17p11, RNASEL at 1q25 and MSR1 at 8p22. RNASEL, encoding the 2 0 ,5 0 -oligoadenylate-dependant RNase L, seems to have rare mutations in different ethnicities, such as M1I in Afro-Americans, E265X in men of European descent and 471delAAAG in Ashkenazi Jews. In order to evaluate the relevance of RNASEL in the German population, we sequenced its open reading frame to determine the spectrum and frequency of germline mutations. The screen included 303 affected men from 136 Caucasian families, of which 45 met the criteria for hereditary prostate cancer. Variants were analysed using a family-based association test, and genotyped in an additional 227 sporadic prostate cancer patients and 207 controls. We identified only two sib pairs (1.4% of our families) cosegregating conspicuous RNASEL variants with prostate cancer: the nonsense mutation E265X, and a new amino-acid substitution (R400P) of unknown functional relevance. Both alleles were also found at low frequencies (1.4 and 0.5%, respectively) in controls. No significant association of polymorphisms (I97L, R462Q and D541E) was observed, neither in case -control analyses nor by family-based association tests. In contrast to previous reports, our study does not suggest that common variants (i.e. R462Q) modify disease risk. Our results are not consistent with a high penetrance of deleterious RNASEL mutations. Due to the low frequency of germline mutations present in our sample, RNASEL does not have a significant impact on prostate cancer susceptibility in the German population.
“…91 The third approach to the identification of PC TSGs involves linkage analysis in familial PC pedigrees and positional cloning. 92 Like the study of oncogenes, the study of TSGs in PC will provide insights into the malignant process and potentially generate both prognostic markers and future treatment strategies.…”
Section: Tsgs In Prostate Cancermentioning
confidence: 99%
“…Germline variation in the RNASEL gene segregates in PC families that show linkage to the hereditary prostate cancer (HPC-1) region at 1q24-25. 92 In this case, RNASEL does not act as a 'classical' TSG. Here, possession of a 'high risk' allele simply predisposes to development of PC in the relatively large proportion of the population in which these occur.…”
Development of any cancer reflects a progressive accumulation of alterations in various genes. Oncogenes, tumour suppressor genes, DNA repair genes and metastasis suppressor genes have been investigated in prostate cancer. Here, we review current understanding of the molecular biology of prostate cancer. Detailed understanding of the molecular basis of prostate cancer will provide insights into the aetiology and prognosis of the disease, and suggest avenues for therapeutic intervention in the future.
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