RESUMO
PURPOSE: Steroid hormones, particularly androgens, are suspected to have a major role in prostate carcinogenesis. Since androgen receptor mediates androgenic effects on cells and recent studies suggest that the androgen receptor gene is a putative prostate cancer susceptibility locus, we screened the coding region of the androgen receptor gene for germline mutations using the genomic DNA of patients with prostate cancer. MATERIALS AND METHODS: DNA samples from 38 patients with early onset prostate cancer and 36 from Finnish prostate cancer families showing no male-to-male transmission of prostate cancer were analyzed for mutations in the androgen receptor gene using single strand conformation polymorphism analysis and subsequent sequencing. RESULTS: R726L substitution in the hormone binding region of androgen receptor was found in 1 prostate cancer family but no previously uncharacterized germline mutations were detected. CONCLUSIONS: Our results indicate that constitutional androgen receptor mutations explain only a small fraction of familial and early onset prostate cancer cases in Finland.
Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Idoso , Análise Mutacional de DNA , DNA de Neoplasias/análise , Finlândia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Recently, Kruppel-like factor 6 gene (KLF6) has been shown to be inactivated in up to 77% of prostate carcinomas. KLF6 has an important role in regulating cell growth and differentiation. The function and high mutation frequency in sporadic prostate carcinomas make KLF6 an attractive candidate for prostate cancer predisposition and, therefore, DNA samples from 69 Finnish prostate cancer families were analyzed for KLF6 mutations. MATERIALS AND METHODS: DNA samples from 69 Finnish prostate cancer families were screened for mutations in the KLF6 gene using single-strand conformation polymorphism analysis and confirmatory sequencing. RESULTS: In 8 (11.6%) families single-strand conformation polymorphism shifts were present. Sequencing revealed 6 201G>A (R201R) polymorphisms, as well as a -4C>A and a 956T>C alteration in the 5'- and 3'-untranslated regions, respectively. Nonsense or missense mutations were not found. CONCLUSIONS: Our data suggest that KLF6 germ-line mutations are of marginal importance in prostate cancer predisposition in Finland.
Assuntos
Predisposição Genética para Doença/epidemiologia , Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas , Transativadores/genética , Dedos de Zinco/genética , Adulto , Idoso , Sequência de Bases , Finlândia/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Masculino , Pessoa de Meia-Idade , Polimorfismo Conformacional de Fita Simples , Estudos SoroepidemiológicosRESUMO
Mutations in the androgen receptor (AR) gene have been suggested to predispose to male breast cancer (MBC). Studies on MBC patients have not been based on the mutation screening of the entire coding region of the AR and the number of subjects has been small. Therefore, some AR gene alterations may have remained undetected. In the present study, we have comprehensively screened the entire coding region of the AR gene for mutations and also studied the role of AR CAG and GGC repeat lengths as risk factors for MBC in a cohort of 32 Finnish MBC patients. To estimate the possible involvement of the prostate cancer predisposing AR Arg726Leu germ-line mutation in MBC, this mutation was tested in 117 MBC patients. No germ-line mutations were found and the CAG and GGC repeat lengths were similar among MBC cases as among Scandinavian population. Our data indicate that the AR gene does not substantially contribute to MBC predisposition.
Assuntos
Neoplasias da Mama Masculina/genética , Mutação/genética , Receptores Androgênicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/diagnóstico , Estudos de Coortes , Finlândia , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Fatores de RiscoRESUMO
Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment.