Summary Using age-adjusted incidence rates and proportional incidence ratios, the risks

Prostates obtained at autopsy from black and white males in the United States of America, from Colombians, from Japanese migrants in Hawaii, and from Japanese in Japan (all over 50 years old) were serially step-sectioned and examined microscopically using identical techniques and diagnostic criteria. The age-adjusted overall prevalence of latent carcinoma was significantly higher in US blacks (36.9%), in US whites (34.6%) and in Colombians (31.5%) than in Japanese in Japan (20.5%). There was no significant difference in prevalence between Japanese migrants in Hawaii (25.6%) and Japanese in Japan. When the carcinomas were subdivided into latent infiltrative type (LIT) and latent non-infiltrative type (LNT), the LIT component reflected upon the overall prevalence of latent carcinoma. There was an increase in the overall prevalence of latent carcinoma and in the prevalence of LIT tumors with age in Japanese migrants to Hawaii and in Japanese of Japan but only a suggestive increase in blacks and whites in the United States. There was no significant relation between age and prevalence in Colombia. In LNT tumors, there was no consistent trend related to race or age. The size of LIT tumors was significantly greater than that of LNT tumors in all races or in each decade of total material. There were many large LIT tumors in blacks and whites in the United States. These results suggest that the prevalence of LIT tumors shows a race variation similar to the incidence of clinical carcinoma of the prostate, and that LNT tumors probably remain latent during the individual's life span.

SUMMARY:Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. Heterogenous expression of androgen receptor (AR), which appears to be related to variable responses to endocrine therapy in prostate cancer (PCa) may also be due to epigenetic factors. The methylation status of the 5Ј CpG island of the AR in 3 prostate cancer cell lines and 10 primary and 14 hormone-refractory PCa samples was determined using the bisulfite PCR methods. In DU145, CpG-rich regions of the AR were hypermethylated. By an immunohistochemical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylationspecific PCR analysis showed aberrant methylation of AR 5Ј-regulatory region in 20% of 10 primary and 28% of 14 hormone-refractory PCa samples. To clarify the effect of epigenetic regulation on AR expression, we treated three prostate cancer cell lines with a demethylating agent, 5-aza-2Ј-deoxycytidine (azaC), and a histone deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of AR mRNA was detected after treatment with azaC and/or TSA. Our results suggest that epigenetic regulations including CpG methylation and histone acetylation may play important roles in the regulation of the AR.

Thyroid glands obtained from patients in southeastern Canada, northeastern Japan, southern Poland, western Colombia, and from Japanese living in Hawaii were serially step-sectioned and examined microscopically using identical techniques and diagnostic criteria. The prevalence of occult papillary thyroid carcinoma was significantly higher in Japan (28.4%) and in Hawaiian Japanese (24.2%) when compared with Canada (6%), Poland (9.1%), and Colombia (5.6%). The carcinomas were all papillary except for a single follicular lesion from Colombia. There was no significant sex prevalence. Most of the patients were between 40 and 79 years of age, but there was no particular predominant decade. Only the Colombian series had a large number of younger patients, and they showed a slightly lower prevalence of occult carcinomas before age 40. Most papillary thyroid carcinomas grow slowly and probably remain occult for the life of the patient.

SUMMARY:The retinoic acid receptor (RAR) ␤ gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RAR␤, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RAR␤ mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RAR␤2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RAR␤2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2'-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RAR␤2 in RAR␤2-negative cells. These data suggest that the RAR␤2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa. (Lab Invest 2001, 81:1049 -1057.