RESUMEN
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Pruebas Genéticas , Humanos , Calicreínas/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de Secreción Prostática/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de RiesgoRESUMEN
BACKGROUND: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. METHODS: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C>T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. RESULTS: The prevalence of MSR1*999C>T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C>T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). CONCLUSION: Our large-scale analysis of case and controls from several countries found no evidence that the 999C>T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk.
Asunto(s)
Neoplasias de la Próstata/genética , Receptores Inmunológicos/genética , Anciano , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Próstata/epidemiología , Receptores Depuradores , Factores de Riesgo , Receptores Depuradores de Clase ARESUMEN
Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).
Asunto(s)
Genoma Humano , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Cromosomas Humanos , Susceptibilidad a Enfermedades , Genotipo , Humanos , MasculinoRESUMEN
Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.
Asunto(s)
Neoplasias de la Mama/genética , Cromosomas Humanos Par 8 , Neoplasias Colorrectales/genética , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Adulto , Anciano , Estudios de Casos y Controles , Mapeo Cromosómico , Cromosomas Humanos Par 8/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at =60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Sitios de Carácter Cuantitativo , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Australia , Estudios de Casos y Controles , Mapeo Cromosómico , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reino UnidoRESUMEN
This review describes what is currently known about the genetics of prostate cancer. Traditionally, the genetics of a suspected inherited cancer predisposition have generally been thought of in terms of a single, high-risk gene with a dominant mode of inheritance. Such a gene might be observed in families, as has been documented in familial breast cancer (BRCA1/2), familial colorectal cancer (HNPCC), retinoblastoma (RB1), and Wilms tumor (WT1). This review investigates the evidence for the existence, first of familial prostate cancer, and second, for the presence of such a high-risk gene in those families by epidemiological and experimental approaches. Another current area of interest in prostate cancer is the investigation of the contribution of common lower penetrance genes to the disease. This alternative approach has become popular, as it raises the issue of frequently seen genetic variations such as single nucleotide polymorphisms (SNPs) having relevance to the risk of developing the disease. Finally, this article will explore the way forward, with emphasis on worldwide collaboration from teams attempting to find the genes responsible for the disease and investment in new technologies that will aid in their discovery.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Humanos , Masculino , Penetrancia , Neoplasias de la Próstata/diagnósticoRESUMEN
Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were =55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.