RESUMO
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
Assuntos
Endorribonucleases/genética , Mutação em Linhagem Germinativa , Oncogenes , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Nucleotídeos de Adenina/metabolismo , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Ligação Genética , Heterozigoto , Homozigoto , Humanos , Perda de Heterozigosidade , Linfócitos/enzimologia , Masculino , Oligorribonucleotídeos/metabolismo , LinhagemRESUMO
The aim of this study was to develop a saturated transcript map of the region encompassing the HPC1 locus to identify the susceptibility genes involved in hereditary prostate cancer (OMIM 176807) and hyperparathyroidism-jaw tumor syndrome (OMIM 145001). We previously reported the generation of a 6-Mb BAC/PAC contig of the candidate region and employed various strategies, such as database searching, exon-trapping, direct cDNA hybridization, and sample sequencing of BACs, to identify all potential transcripts. These efforts led to the identification and precise localization on the BAC contig of 59 transcripts representing 22 known genes and 37 potential transcripts represented by ESTs and exon traps. Here we report the detailed characterization of these ESTs into full-length transcript sequences, their expression pattern in various tissues, their genomic organization, and their homology to known genes. We have also identified an Alu insertion polymorphism in the intron of one of the transcripts. Overall, data on 13 novel transcripts and the human RGS8 gene (homologue of the rat RGS8 gene) are presented in this paper. Ten of the 13 novel transcripts are expressed in prostate tissue and represent positional candidates for HPC1.
Assuntos
Cromossomos Humanos Par 1 , Síndromes Neoplásicas Hereditárias/genética , Neoplasias da Próstata/genética , Proteínas RGS/genética , tRNA Metiltransferases/genética , Sequência de Aminoácidos , Animais , Mapeamento de Sequências Contíguas , DNA Complementar , Etiquetas de Sequências Expressas , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença , Genoma Humano , Humanos , Hiperparatireoidismo/genética , Neoplasias Maxilomandibulares/genética , Masculino , Dados de Sequência Molecular , Mutação , Neoplasias das Paratireoides/genética , Ratos , Homologia de Sequência de Aminoácidos , Transcrição GênicaRESUMO
A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Genetics & Development.
Assuntos
Oncogenes , Divisão Celular , InternetRESUMO
Several hereditary disease loci have been genetically mapped to the chromosome 1q24-q31 interval, including the hereditary prostate cancer 1 (HPC1) locus. Here, we report the construction of a 20-Mb yeast artificial chromosome contig and a high-resolution 6-Mb sequence-ready bacterial artificial chromosome (BAC)/P1-derived artificial chromosome (PAC) contig of 1q25 by sequence and computational analysis, STS content mapping, and chromosome walking. One hundred thirty-six new STSs, including 10 novel simple sequence repeat polymorphisms that are being used for genetic refinement of multiple disease loci, have been generated from this contig and are shown to map to the 1q25 interval. The integrity of the 6-Mb BAC/PAC contig has been confirmed by restriction fingerprinting, and this contig is being used as a template for human chromosome 1 genome sequencing. A transcription mapping effort has resulted in the precise localization of 18 known genes and 31 ESTs by database searching, exon trapping, direct cDNA hybridization, and sample sequencing of BACs from the 1q25 contig. An additional 11 known genes and ESTs have been placed within the larger 1q24-q31 interval. These transcription units represent candidate genes for multiple hereditary diseases, including HPC1.