Molecular disorders in transitionalvs. peripheral zone prostate adenocarcinoma

Abstract

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been shown to be mechanisms for tumor-suppressor gene inactivation in human oncogenesis. In our study, we examined LOH and MSI using 16 polymorphic markers of DNA for chromosomes 1, 3, 7, 8, 10 and 11. Microdissected tumor samples were isolated from 32 patients, representing 11 foci of incidentally discovered prostate cancer of the transitional zone (TZ), 12 prostate cancer of the peripheral zone (PZ) and 10 of high-grade PIN. We found loss of heterozygosity in the TZ group in 91% of informative cases (10/11) with al least 1 marker compared to 58% of cases (7/12) in PZ group and 70% of cases (7/10) in the HGPIN group. Chromosome 7 showed the highest rate of allelic loss in all 3 categories, with loss of 43% of loci in PIN, 37% in TZ tumors and 31% in PZ tumors. At chromosome 11, LOH was detected in 26% of loci in the TZ group, in 7% of loci in the PZ group and in 13% of loci in the PIN group. On chromosome 8, the PZ and HGPIN group showed allelic loss in 22% and 21% of loci, respectively, compared to 10% detected in the TZ group. The TZ group showed a significant higher rate of allelic instability compared to that observed in tumor samples from the peripheral zone: 73% of cases (8/11) showed genetic alterations (RER؉ phenotype) in at least 4 loci analyzed compared to 8% and 10% in the PZ and HGPIN groups, respectively (p ‫؍‬ 0.0006). These data suggest that transitional zone carcinoma and peripheral zone carcinoma display distinct and specific genetic alterations in different chromosomes. This diversity may help explain biologic and clinical differences between carcinomas arising in these distinct zones of the prostate. Also our results strongly suggest that the RER؉ mutator phenotype could be linked to early development of transitional zone prostate carcinoma.

Function of JunB in Transient Amplifying Cell Senescence and Progression of Human Prostate Cancer

“…The persistent growth arrest characteristic of clones obtained from the CZ was reversed by inactivation of junB by siRNA transfection. Distinct and specific genetic alterations in different chromosomes have been detected between PZ and TZ carcinomas (22), and basal cells Fig. 4.…”

“…Most predominant and aggressive cancers occur in the PZ, with less aggressive cancers and benign prostatic hyperplasia occurring exclusively in the TZ and much less in the CZ. This suggests different molecular mechanisms based on distinct and specific genetic alterations (22,23). Therefore, examination of TAC derived from the biologically different zones may give insights into the mechanisms underlying prostate carcinogenesis.…”

Population-Based Study of the Association of Variants in Mismatch Repair Genes with Prostate Cancer Risk and Outcomes

“…This damaged DNA can accumulate and eventually lead to the development of neoplasms, such as hereditary nonpolyposis colon cancer (HNPCC), which is characterized by mutations in five microsatellites [3]. A number of studies have reported more MSI in PC tumor tissue compared to normal prostatic tissue [4-9], but some PC tissue studies have found a low frequency of MSI [10-14]. In addition, reduction or loss of MMR protein expression has been found in human PC cell lines, such as LNCaP, PC-3 and DU145 [15-20].…”

Molecular biology of prostate cancer

“…The above MMR phenotype may be linked to early development of transitional zone PC. 289 Wille et al 290 evaluated MSI as a marker to estimate the cancer risk in PC families. They studied seven first-degree relatives of PC probands and found 28% tumour MSI, suggesting that MSI is not more common when two first-degree relatives have PC than in sporadic PC.…”