共查询到20条相似文献,搜索用时 31 毫秒
1.
Prostate cancer is a complex disease to which a multitude of genetic and environmental factors contribute. Two new studies offer insights as to how the disease may arise and progress. The first describes mapping and cloning of a new candidate gene, ELAC2, whereas the second demonstrates how cooperation between Cdkn1b and Pten contribute to suppression of prostate tumors. 相似文献
2.
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. 总被引:21,自引:0,他引:21
W J Song M G Sullivan R D Legare S Hutchings X Tan D Kufrin J Ratajczak I C Resende C Haworth R Hock M Loh C Felix D C Roy L Busque D Kurnit C Willman A M Gewirtz N A Speck J H Bushweller F P Li K Gardiner M Poncz J M Maris D G Gilliland 《Nature genetics》1999,23(2):166-175
3.
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
4.
Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer 总被引:7,自引:0,他引:7
Huusko P Ponciano-Jackson D Wolf M Kiefer JA Azorsa DO Tuzmen S Weaver D Robbins C Moses T Allinen M Hautaniemi S Chen Y Elkahloun A Basik M Bova GS Bubendorf L Lugli A Sauter G Schleutker J Ozcelik H Elowe S Pawson T Trent JM Carpten JD Kallioniemi OP Mousses S 《Nature genetics》2004,36(9):979-983
The identification of tumor-suppressor genes in solid tumors by classical cancer genetics methods is difficult and slow. We combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for the genome-wide identification of genes with biallelic inactivation involving nonsense mutations and loss of the wild-type allele. This approach enabled us to identify previously unknown mutations in the receptor tyrosine kinase gene EPHB2. The DU 145 prostate cancer cell line, originating from a brain metastasis, carries a truncating mutation of EPHB2 and a deletion of the remaining allele. Additional frameshift, splice site, missense and nonsense mutations are present in clinical prostate cancer samples. Transfection of DU 145 cells, which lack functional EphB2, with wild-type EPHB2 suppresses clonogenic growth. Taken together with studies indicating that EphB2 may have an essential role in cell migration and maintenance of normal tissue architecture, our findings suggest that mutational inactivation of EPHB2 may be important in the progression and metastasis of prostate cancer. 相似文献
5.
Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes 总被引:1,自引:0,他引:1
Gudmundsson J Sulem P Steinthorsdottir V Bergthorsson JT Thorleifsson G Manolescu A Rafnar T Gudbjartsson D Agnarsson BA Baker A Sigurdsson A Benediktsdottir KR Jakobsdottir M Blondal T Stacey SN Helgason A Gunnarsdottir S Olafsdottir A Kristinsson KT Birgisdottir B Ghosh S Thorlacius S Magnusdottir D Stefansdottir G Kristjansson K Bagger Y Wilensky RL Reilly MP Morris AD Kimber CH Adeyemo A Chen Y Zhou J So WY Tong PC Ng MC Hansen T Andersen G Borch-Johnsen K Jorgensen T Tres A Fuertes F 《Nature genetics》2007,39(8):977-983
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes. 相似文献
6.
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
7.
Ruiz-Perez VL Ide SE Strom TM Lorenz B Wilson D Woods K King L Francomano C Freisinger P Spranger S Marino B Dallapiccola B Wright M Meitinger T Polymeropoulos MH Goodship J 《Nature genetics》2000,24(3):283-286
Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions. 相似文献
8.
Kondo Y Shen L Cheng AS Ahmed S Boumber Y Charo C Yamochi T Urano T Furukawa K Kwabi-Addo B Gold DL Sekido Y Huang TH Issa JP 《Nature genetics》2008,40(6):741-750
Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation. 相似文献
9.
Hazan J Fonknechten N Mavel D Paternotte C Samson D Artiguenave F Davoine CS Cruaud C Dürr A Wincker P Brottier P Cattolico L Barbe V Burgunder JM Prud'homme JF Brice A Fontaine B Heilig B Weissenbach J 《Nature genetics》1999,23(3):296-303
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes. 相似文献
10.
Mutations truncating the EP300 acetylase in human cancers 总被引:21,自引:0,他引:21
Gayther SA Batley SJ Linger L Bannister A Thorpe K Chin SF Daigo Y Russell P Wilson A Sowter HM Delhanty JD Ponder BA Kouzarides T Caldas C 《Nature genetics》2000,24(3):300-303
11.
Thomas G Jacobs KB Yeager M Kraft P Wacholder S Orr N Yu K Chatterjee N Welch R Hutchinson A Crenshaw A Cancel-Tassin G Staats BJ Wang Z Gonzalez-Bosquet J Fang J Deng X Berndt SI Calle EE Feigelson HS Thun MJ Rodriguez C Albanes D Virtamo J Weinstein S Schumacher FR Giovannucci E Willett WC Cussenot O Valeri A Andriole GL Crawford ED Tucker M Gerhard DS Fraumeni JF Hoover R Hayes RB Hunter DJ Chanock SJ 《Nature genetics》2008,40(3):310-315
12.
Carvalho AB 《Nature genetics》2003,34(2):128-129
The macrophage scavenger receptor 1 gene (MSR1) was recently identified as a candidate susceptibility gene for hereditary prostate cancer and as a risk factor for sporadic prostate cancer. To confirm these findings, we screened MSR1 for germline mutations among individuals with familial prostate cancer and tested gene variants for associations in both sporadic and familial prostate cancer. Our results do not support MSR1 as a risk factor for prostate cancer. 相似文献
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14.
Barbieri CE Baca SC Lawrence MS Demichelis F Blattner M Theurillat JP White TA Stojanov P Van Allen E Stransky N Nickerson E Chae SS Boysen G Auclair D Onofrio RC Park K Kitabayashi N MacDonald TY Sheikh K Vuong T Guiducci C Cibulskis K Sivachenko A Carter SL Saksena G Voet D Hussain WM Ramos AH Winckler W Redman MC Ardlie K Tewari AK Mosquera JM Rupp N Wild PJ Moch H Morrissey C Nelson PS Kantoff PW Gabriel SB Golub TR Meyerson M Lander ES Getz G Rubin MA Garraway LA 《Nature genetics》2012,44(6):685-689
15.
Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ Greenway SC Stram DO Le Marchand L Kolonel LN Frasco M Wong D Pooler LC Ardlie K Oakley-Girvan I Whittemore AS Cooney KA John EM Ingles SA Altshuler D Henderson BE Reich D 《Nature genetics》2007,39(5):638-644
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein. 相似文献
16.
Casey G Neville PJ Plummer SJ Xiang Y Krumroy LM Klein EA Catalona WJ Nupponen N Carpten JD Trent JM Silverman RH Witte JS 《Nature genetics》2002,32(4):581-583
RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk. 相似文献
17.
Yeager M Orr N Hayes RB Jacobs KB Kraft P Wacholder S Minichiello MJ Fearnhead P Yu K Chatterjee N Wang Z Welch R Staats BJ Calle EE Feigelson HS Thun MJ Rodriguez C Albanes D Virtamo J Weinstein S Schumacher FR Giovannucci E Willett WC Cancel-Tassin G Cussenot O Valeri A Andriole GL Gelmann EP Tucker M Gerhard DS Fraumeni JF Hoover R Hunter DJ Chanock SJ Thomas G 《Nature genetics》2007,39(5):645-649
Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%). 相似文献
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19.
Hanks S Coleman K Reid S Plaja A Firth H Fitzpatrick D Kidd A Méhes K Nash R Robin N Shannon N Tolmie J Swansbury J Irrthum A Douglas J Rahman N 《Nature genetics》2004,36(11):1159-1161
Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development. 相似文献
20.
The genetic bases underlying prostate tumorigenesis are poorly understood. Inactivation of the tumor-suppressor gene PTEN and lack of p27(KIP1) expression have been detected in most advanced prostate cancers. But mice deficient for Cdkn1b (encoding p27(Kip1)) do not develop prostate cancer. PTEN activity leads to the induction of p27(KIP1) expression, which in turn can negatively regulate the transition through the cell cycle. Thus, the inactivation of p27(KIP1) may be epistatic to PTEN in the control of the cell cycle. Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins. Cell proliferation, but not cell survival, is increased in Pten(+/-)/Cdkn1b(-/-) mice. Moreover, Pten(+/-)/Cdkn1b(-/-) mice develop prostate carcinoma at complete penetrance within three months from birth. These cancers recapitulate the natural history and pathological features of human prostate cancer. Our findings reveal the crucial relevance of the combined tumor-suppressive activity of Pten and p27(Kip1) through the control of cell-cycle progression. 相似文献