RESUMO
In this study, we used 7 informative microsatellite markers at 8p22, 23.1, and 23.2 in Japanese patients to compare frequency of loss of heterozygosity (LOH) in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC), 31 cases (41 lesions) of latent prostate cancer (LPC), and 102 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 8p22-23.2 with at least 1 marker was 0%, 33%, 57%, and 51% in the HGPIN, IPC, LPC, and CPC cases, respectively. No statistically significant difference was found at 8p22-23.2 between the types of prostate cancer. However, the frequency of 8p22 deletion was significantly higher in CPC and LPC cases than in IPC cases (P = 0.0003) or lesions (P = 0.0017). The frequency of LOH at 8p22 and 8p23.1 loci in high-grade tumors was significantly higher than in low-grade tumors in both the LPCs/IPCs and CPCs (P < 0.05). Allelic loss at 8p22 was significantly more frequent in CPC than in IPC (P = 0.002) and in pT4 CPC than in earlier-stage CPC (P = 0.038). These findings suggest that deletion of 8p is an important event in both the initiation and metastasis of prostate cancer. The extremely high frequency of LOH at 8p22-23.1 in high-grade tumors suggests the existence of a novel putative tumor-suppressor gene associated with the progression of prostate cancer. These results should be useful in identifying the target gene of deletion at 8p.
Assuntos
Alelos , Cromossomos Humanos Par 8 , Neoplasia Prostática Intraepitelial/genética , Sequência de Bases , Primers do DNA , Humanos , Perda de Heterozigosidade , Masculino , Reação em Cadeia da Polimerase , Neoplasia Prostática Intraepitelial/patologiaRESUMO
BACKGROUND: Loss of heterozygosity (LOH) at 13q is one of the most common chromosomal alterations in high-stage prostate cancer, yet little is known about genetic changes in earlier-stage prostate cancer. METHODS: We used five microsatellite markers at 13q14, 21, and 33 to compare LOH frequencies in 51 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 21 cases of incidental prostate cancers (IPCs), 31 cases of latent prostate cancers (LPCs), and 102 cases of clinical prostate cancers (CPCs). RESULTS: The frequency of LOH at 13q with at least 1 marker was 0%, 38%, 56%, and 49% in HGPIN, IPCs, LPCs, and CPCs, respectively. No statistically significant difference was found between the types of prostate cancer. Allelic loss at 13q14 was significantly more frequent in pT4 tumors than in earlier-stage tumors (P=0.011). CONCLUSIONS: Allelic loss at 13q is not only an important event in the metastasis of prostate cancer, but also associated with the initiation of the tumor.
Assuntos
Cromossomos Humanos Par 13 , Perda de Heterozigosidade , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Alelos , Transformação Celular Neoplásica/genética , Humanos , Masculino , Repetições de Microssatélites , Metástase Neoplásica/genética , Reação em Cadeia da Polimerase , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologiaRESUMO
The Eker (Tsc2 mutant) rat model of renal carcinoma is an example of Mendelian dominantly inherited predisposition to a specific cancer. Effects of genetic background on renal carcinogenesis in the Eker rat model (Eker/Eker > Eker/BN strain) indicate the presence in the BN rat genome of a modifier gene(s) that suppresses tumorigenesis. The identification of such a modifier gene(s) might help clarify the diversity of tuberous sclerosis in humans. i) We found that preneoplastic lesions in 8-week-old F1 rats [(Eker x LE) and (Eker x BN)] were more numerous in the LE strain than in the BN strain although the difference was not large. ii) We next administered N-ethyl-N-nitrosourea (ENU; single injection, i.p.) at the age of 4 weeks to amplify the strain difference in tumorigenesis, as we had done in an earlier study to identify the predisposing gene. iii) This experiment was also done in BN congenic Eker rats to confirm the strain difference in tumorigenesis. Preneoplastic lesions were fewer in BN congenic rats than in Eker rats by a factor of 100. We used this ENU system to perform a backcross experiment [F1(Eker x BN) x Eker] and finally succeeded in mapping a new modifier locus on rat chromosome 5 (the LOD score of the D5Rat12 was 3.13).
Assuntos
Carcinoma de Células Renais/patologia , Genes Supressores de Tumor , Neoplasias Renais/patologia , Mutação , Proteínas Repressoras/genética , Alquilantes/administração & dosagem , Animais , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/genética , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Cruzamentos Genéticos , Etilnitrosoureia/administração & dosagem , Feminino , Genótipo , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/genética , Escore Lod , Masculino , Repetições de Microssatélites , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Long-Evans , Ratos Mutantes , Fatores de Tempo , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de TumorRESUMO
The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.
