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Background  Alterations of chromosome 8 and hypomethylation of LINE-1 retrotransposons are common alterations in advanced prostate carcinoma. In a former study including many metastatic cases, they strongly correlated with each other. To elucidate a possible interaction between the two alterations, we investigated their relationship in less advanced prostate cancers.    Results  In 50 primary tumor tissues, no correlation was observed between chromosome 8 alterations determined by comparative genomic hybridization and LINE-1 hypomethylation measured by Southern blot hybridization. The discrepancy towards the former study, which had been dominated by advanced stage cases, suggests that both alterations converge and interact during prostate cancer progression. Therefore, interaction analysis was performed on microarray-based expression profiles of cancers harboring both alterations, only one, or none. Application of a novel bioinformatic method identified Gene Ontology (GO) groups related to innate immunity, cytoskeletal organization and cell adhesion as common targets of both alterations. Many genes targeted by their interaction were involved in type I and II interferon signaling and several were functionally related to hereditary prostate cancer genes. In addition, the interaction appeared to influence a switch in the expression pattern of  EPB41L  genes encoding 4.1 cytoskeleton proteins. Real-time RT-PCR revealed  GADD45A ,  MX1 ,  EPB41L3 / DAL1 , and  FBLN1  as generally downregulated in prostate cancer, whereas  HOXB13  and  EPB41L4B  were upregulated.  TLR3  was downregulated in a subset of the cases and associated with recurrence. Downregulation of  EPB41L3 , but not of  GADD45A , was associated with promoter hypermethylation, which was detected in 79% of carcinoma samples.    Conclusion  Alterations of chromosome 8 and DNA hypomethylation in prostate cancer probably do not cause each other, but converge during progression. The present analysis implicates their interaction in innate immune response suppression and cytoskeletal changes during prostate cancer progression. The study thus highlights novel mechanisms in prostate cancer progression and identifies novel candidate genes for diagnostic and therapeutic purposes. In particular,  TLR3  expression might be useful for prostate cancer prognosis and  EPB41L3  hypermethylation for its detection.

molecular cancer

Factor interaction analysis for chromosome 8 and DNA methylation alterations highlights innate immune response suppression and cytoskeletal changes in prostate cancer.