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Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. 总被引:18,自引:0,他引:18
J Carpten N Nupponen S Isaacs R Sood C Robbins J Xu M Faruque T Moses C Ewing E Gillanders P Hu P Bujnovszky I Makalowska A Baffoe-Bonnie D Faith J Smith D Stephan K Wiley M Brownstein D Gildea B Kelly R Jenkins G Hostetter M Matikainen J Schleutker K Klinger T Connors Y Xiang Z Wang A De Marzo N Papadopoulos O-P Kallioniemi R Burk D Meyers H Gr?nberg P Meltzer R Silverman J Bailey-Wilson P Walsh W Isaacs J Trent 《Nature genetics》2002,30(2):181-184
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. 相似文献
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Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk 总被引:16,自引:0,他引:16
Xu J Zheng SL Komiya A Mychaleckyj JC Isaacs SD Hu JJ Sterling D Lange EM Hawkins GA Turner A Ewing CM Faith DA Johnson JR Suzuki H Bujnovszky P Wiley KE DeMarzo AM Bova GS Chang B Hall MC McCullough DL Partin AW Kassabian VS Carpten JD Bailey-Wilson JE Trent JM Ohar J Bleecker ER Walsh PC Isaacs WB Meyers DA 《Nature genetics》2002,32(2):321-325
Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent. 相似文献
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Carpten JD Robbins CM Villablanca A Forsberg L Presciuttini S Bailey-Wilson J Simonds WF Gillanders EM Kennedy AM Chen JD Agarwal SK Sood R Jones MP Moses TY Haven C Petillo D Leotlela PD Harding B Cameron D Pannett AA Höög A Heath H James-Newton LA Robinson B Zarbo RJ Cavaco BM Wassif W Perrier ND Rosen IB Kristoffersson U Turnpenny PD Farnebo LO Besser GM Jackson CE Morreau H Trent JM Thakker RV Marx SJ Teh BT Larsson C Hobbs MR 《Nature genetics》2002,32(4):676-680
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors. 相似文献
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Replicating genotype-phenotype associations 总被引:1,自引:0,他引:1
NCI-NHGRI Working Group on Replication in Association Studies Chanock SJ Manolio T Boehnke M Boerwinkle E Hunter DJ Thomas G Hirschhorn JN Abecasis G Altshuler D Bailey-Wilson JE Brooks LD Cardon LR Daly M Donnelly P Fraumeni JF Freimer NB Gerhard DS Gunter C Guttmacher AE Guyer MS Harris EL Hoh J Hoover R Kong CA Merikangas KR Morton CC Palmer LJ Phimister EG Rice JP Roberts J Rotimi C Tucker MA Vogan KJ Wacholder S Wijsman EM Winn DM Collins FS 《Nature》2007,447(7145):655-660
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