Genomewide DNA hypomethylation is associated with alterations on chromosome 8 in prostate carcinoma

To elucidate the relationship between genomewide DNA hypomethylation and chromosome instability, 55 prostate carcinoma specimens were analyzed for extent of hypomethylation by Southern blot analysis of LINE‐1 sequence methylation and for loss or gain of chromosomal material by comparative genomic hybridization. Seventeen (31%) tumors showed strong hypomethylation of DNA, whereas four (7%) displayed slight hypomethylation and the rest of the tumors normal‐level methylation. Chromosomal aberrations were observed in 34 carcinomas. The most frequent chromosomal alterations were loss of 13q in 18 cases and aberrations in 8p (loss) or 8q (gain) in 16 cases. The presence of chromosomal loss or gain was significantly associated with the presence of strong hypomethylation. A striking correlation (P = 0.00001) was observed between aberrations on chromosome 8 and hypomethylation, whereas no association was seen between DNA hypomethylation and loss of 13q. The association between DNA hypomethylation and the presence of metastases was statistically significant (P = 0.044), and both chromosomal alterations and DNA hypomethylation tended to be more frequent in higher‐stage tumors. In conclusion, the data indicate that hypomethylation is associated with chromosomal instability in prostate cancer. Specifically, a surprisingly strong association between alterations on chromosome 8 and genomewide hypomethylation was found. This association suggests that DNA hypomethylation and alterations in chromosome 8 may be mechanistically linked to each other in prostate carcinoma. © 2002 Wiley‐Liss, Inc.

[1]  W. Schulz,et al.  Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder , 2001, British Journal of Cancer.

[2]  D. Takai,et al.  Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. , 2001, Human molecular genetics.

[3]  W. Lau,et al.  Hypomethylation of chromosome 1 heterochromatin DNA correlates with q-arm copy gain in human hepatocellular carcinoma. , 2001, The American journal of pathology.

[4]  S. Saga,et al.  Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma , 2001, British Journal of Cancer.

[5]  Keith D Robertson,et al.  DNA methylation, methyltransferases, and cancer , 2001, Oncogene.

[6]  Y. Liaw,et al.  Genome-wide hypomethylation in hepatocellular carcinogenesis. , 2001, Cancer research.

[7]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[8]  S. Hirohashi,et al.  DNA methyltransferase expression and DNA methylation of CPG islands and peri‐centromeric satellite regions in human colorectal and stomach cancers , 2001, International journal of cancer.

[9]  W. Schulz,et al.  DNA Methylation and the Mechanisms of CDKN2A Inactivation in Transitional Cell Carcinoma of the Urinary Bladder , 2000, Laboratory Investigation.

[10]  B. Eussen,et al.  Characterization of a zinc-finger protein and its association with apoptosis in prostate cancer cells. , 2000, Journal of the National Cancer Institute.

[11]  K. Pienta,et al.  Genetic characterization of immortalized human prostate epithelial cell cultures. Evidence for structural rearrangements of chromosome 8 and i(8q) chromosome formation in primary tumor-derived cells. , 2000, Cancer genetics and cytogenetics.

[12]  H. Tanke,et al.  Identification of Genetic Markers for Prostatic Cancer Progression , 2000, Laboratory Investigation.

[13]  N. Tommerup,et al.  Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene , 1999, Nature.

[14]  D. Bostwick,et al.  Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. , 1999, Journal of the National Cancer Institute.

[15]  R. Löwer,et al.  DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas , 1999, British Journal of Cancer.

[16]  K. Porkka,et al.  Amplification and overexpression of p40 subunit of eukaryotic translation initiation factor 3 in breast and prostate cancer. , 1999, The American journal of pathology.

[17]  W. Schulz,et al.  High frequency of alterations in DNA methylation in adenocarcinoma of the prostate , 1999, The Prostate.

[18]  M. Ehrlich,et al.  Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16. , 1999, Cancer genetics and cytogenetics.

[19]  M. Ehrlich,et al.  Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential. , 1999, Mutation research.

[20]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[21]  W. Schulz,et al.  DNA methylation in urological malignancies (review). , 1998, International journal of oncology.

[22]  T. Visakorpi,et al.  Genetic alterations in hormone-refractory recurrent prostate carcinomas. , 1998, The American journal of pathology.

[23]  M. Loda,et al.  Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  E. Bergstralh,et al.  Prognostic significance of allelic imbalance of chromosome arms 7q, 8p, 16q, and 18q in stage T3N0M0 prostate cancer , 1998, Genes, chromosomes & cancer.

[25]  R. T. Curtis,et al.  A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. , 1997, Genomics.

[26]  L. Glória,et al.  Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma. , 1996, Gut.

[27]  P. Carroll,et al.  Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. , 1996, Cancer research.

[28]  T. Visakorpi,et al.  Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. , 1995, Cancer research.

[29]  A. Feinberg,et al.  Reduced genomic 5-methylcytosine content in human colonic neoplasia. , 1988, Cancer research.

[30]  P. V. van Helden,et al.  Hypomethylation of DNA in pathological conditions of the human prostate. , 1987, Cancer research.