RESUMEN
BACKGROUND: Allogeneic therapeutic cells may be rejected if they express HLA alleles not found in the recipient. As finding cell donors with a full HLA match to a recipient requires vast donor pools, the use of HLA homozygous cells has been suggested as an alternative. HLA homozygous cells should be well tolerated by those who carry at least one copy of donor HLA alleles. HLA-A-B homozygotes could be valuable for HLA-matched thrombocyte products. We evaluated the feasibility of blood donor biobank and HLA imputation for the identification of potential cell donors homozygous for HLA alleles. METHODS: We imputed HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1 alleles from genotypes of 20,737 Finnish blood donors in the Blood Service Biobank. We confirmed homozygosity by sequencing HLA alleles in 30 samples and by examining 36,161 MHC-located polymorphic DNA markers. RESULTS: Three hundred and seventeen individuals (1.5%), representing 41 different haplotypes, were found to be homozygous for HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1 alleles. Ten most frequent haplotypes homozygous for HLA-A to -DQB1 were HLA-compatible with 49.5%, and three most frequent homozygotes to 30.4% of the Finnish population. Ten most frequent HLA-A-B homozygotes were compatible with 75.3%, and three most frequent haplotypes to 42.6% of the Finnish population. HLA homozygotes had a low level of heterozygosity in MHC-located DNA markers, in particular in HLA haplotypes enriched in Finland. CONCLUSIONS: The present study shows that HLA imputation in a blood donor biobank of reasonable size can be used to identify HLA homozygous blood donors suitable for cell therapy, HLA-typed thrombocytes and research. The homozygotes were HLA-compatible with a large fraction of the Finnish population. Regular blood donors reported to have positive attitude to research donation appear a good option for these purposes. Differences in population frequencies of HLA haplotypes emphasize the need for population-specific collections of HLA homozygous samples.
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Bancos de Muestras Biológicas , Donantes de Sangre , Marcadores Genéticos , Antígenos HLA-A/genética , Homocigoto , HumanosRESUMEN
Concerns over future healthcare capacity along with continuing demands for sustainability call for novel solutions to improve citizens' health and wellbeing through effective prevention and improved diagnosis and treatment. Part of the solution to tackle the challenge could be making the most of the exploitation of genomic data in personalized risk assessment, creating new opportunities for data-driven precision prevention and public health. Presently, the utilization of genomic data in the Finnish healthcare system is limited to a few medical specialty areas. To successfully extend the use of genomic information in everyday healthcare, evidence-based and feasible strategies are needed. The national actions that Finland is taking towards this goal are 1) providing scientific evidence for the utility of genomic information for healthcare purposes; 2) evaluating the potential health-economic impact of implementing precision healthcare in Finland; 3) developing a relevant legal framework and infrastructures for the utilization of genomic information; 4) building a national multidisciplinary expert network bringing together relevant professionals and initiatives to achieve consensus among the different stakeholders on specific issues vital for translating genomic data into precision healthcare; 5) building competence and genomic literacy skills among various target groups; and 6) public engagement (informing and educating the public). Taken together, these actions will enable building a roadmap towards the expedient application of genomic data in Finnish healthcare and promoting the health of our citizens.
RESUMEN
Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.
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Reparación del ADN/genética , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Anciano , Finlandia/epidemiología , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Suecia/epidemiología , Secuenciación del ExomaRESUMEN
Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.
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Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Serina Endopeptidasas/genética , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Neoplasias de la Próstata/patología , Sitios de Carácter Cuantitativo/genética , Regulador Transcripcional ERG/genéticaRESUMEN
A total of nine non-coding variants on 11q13.5 predispose men to prostate cancer (PrCa). rs200331695 within the EMSY intron is associated with aggressive PrCa and two high linkage disequilibrium (LD) groups of single-nucleotide polymorphisms (SNPs) in the intergenic region are associated with PrCa death. Here, the cis-effect of the SNPs on gene expression using expression quantitative trait loci analysis was investigated. The regulatory potential was screened in prostate tumors (n = 41) and in whole blood (n = 99). The results were validated in a second tumor set (n = 41), in lymphoblastoid cell lines (LCLs) (n = 38), and using the GTEx Portal. The effects of haplotypes were analyzed in the whole blood. The high LD SNPs (rs143975731, rs12277366, rs2155225, and rs2155222) were associated with DGAT2 expression in both tumors sets (screening P = 0.035-0.043; validation P = 0.005-0.018). The PrCa death-associated alleles decreased the expression by two-fold. rs200331695 decreased DGAT2 expression in LCLs (P = 0.006). The findings of SNPs regulating CAPN5 (P = 0.026-0.046) and AP001189.4 (P = 0.03-0.039) in the whole blood were not observed in LCLs, but the association with AP001189.4 expression was validated via the GTEx Portal (P = 8.7 × 10(-5) to 4.3 × 10(-4) ), which suggests that the high LD intergenic SNPs exert a tissue-dependent effect on the expression of two genes. No haplotypes including the risk SNPs at 11q13.5 were associated with gene expression and PrCa. The findings indicate the functionality of the PrCa death-predisposing SNPs rs143975731, rs12277366, rs2155225, and rs2155222 as DGAT2 regulators in prostate tumors. © 2016 Wiley Periodicals, Inc.
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Diacilglicerol O-Acetiltransferasa/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/genética , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 11/genética , Diacilglicerol O-Acetiltransferasa/biosíntesis , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.
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Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/metabolismo , Proteínas de Secreción Prostática/sangre , Proteínas de Secreción Prostática/metabolismo , Andrógenos/metabolismo , Biopsia con Aguja , Línea Celular Tumoral , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Inmunohistoquímica , Masculino , Metástasis de la Neoplasia , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia , Coactivadores de Receptor Nuclear/metabolismo , Polimorfismo de Nucleótido Simple , Prostatectomía , Hiperplasia Prostática/metabolismo , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: The inherited factors that predispose individuals to prostate cancer (PrCa) remain largely unknown. The aim of this study was to identify germline copy number variants (CNVs) in Finnish individuals that could contribute to an increased PrCa risk. METHODS: Genome-wide CNV screening was performed by analyzing single nucleotide polymorphisms from 105 PrCa patients and 37 unaffected relatives, representing 31 Finnish hereditary PrCa (HPC) families. The CNVs that aggregated in affected individuals and overlapped with genes implicated in cancer were validated using quantitative PCR in 189 index patients from Finnish HPC families and in 476 controls. RESULTS: An intronic deletion (14.7 kb) in the EPHA3 gene coding for class A ephrin receptor was observed in 11.6% of PrCa patients and in 6.1% of controls. The deletion associated with an increased PrCa risk (P = 0.018, OR = 2.06, 95%CI = 1.18-3.61). Although incomplete segregation with affection status was observed, the results show that the deletion was overrepresented in PrCa patients (56.1%) when compared to unaffected male relatives (31.2%). Interestingly, PrCa-specific mortality was higher among EPHA3 deletion carriers (24.3%) than among patients with a normal EPHA3 copy number (3.4%). CONCLUSIONS: This study is the first investigation of the contribution of germline CNVs to HPC susceptibility in Finland. A novel association between the EPHA3 deletion and PrCa risk was observed and, if confirmed, screening for this variant may aid in risk stratification among HPC patients.
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Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Neoplasias de la Próstata/genética , Proteínas Tirosina Quinasas Receptoras/genética , Población Blanca/genética , Anciano , Femenino , Finlandia/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Receptor EphA3 , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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Marcadores Genéticos , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Variación Genética , Humanos , Desequilibrio de Ligamiento , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Heritable factors are evidently involved in prostate cancer (PrCa) carcinogenesis, but currently, genetic markers are not routinely used in screening or diagnostics of the disease. More precise information is needed for making treatment decisions to distinguish aggressive cases from indolent disease, for which heritable factors could be a useful tool. The genetic makeup of PrCa has only recently begun to be unravelled through large-scale genome-wide association studies (GWAS). The thus far identified Single Nucleotide Polymorphisms (SNPs) explain, however, only a fraction of familial clustering. Moreover, the known risk SNPs are not associated with the clinical outcome of the disease, such as aggressive or metastasised disease, and therefore cannot be used to predict the prognosis. Annotating the SNPs with deep clinical data together with miRNA expression profiles can improve the understanding of the underlying mechanisms of different phenotypes of prostate cancer. RESULTS: In this study microRNA (miRNA) profiles were studied as potential biomarkers to predict the disease outcome. The study subjects were from Finnish high risk prostate cancer families. To identify potential biomarkers we combined a novel non-parametrical test with an importance measure provided from a Random Forest classifier. This combination delivered a set of nine miRNAs that was able to separate cases from controls. The detected miRNA expression profiles could predict the development of the disease years before the actual PrCa diagnosis or detect the existence of other cancers in the studied individuals. Furthermore, using an expression Quantitative Trait Loci (eQTL) analysis, regulatory SNPs for miRNA miR-483-3p that were also directly associated with PrCa were found. CONCLUSION: Based on our findings, we suggest that blood-based miRNA expression profiling can be used in the diagnosis and maybe even prognosis of the disease. In the future, miRNA profiling could possibly be used in targeted screening, together with Prostate Specific Antigene (PSA) testing, to identify men with an elevated PrCa risk.
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Familia , Regulación Neoplásica de la Expresión Génica , MicroARNs , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata , ARN Neoplásico , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular , Finlandia , Perfilación de la Expresión Génica , Humanos , Masculino , MicroARNs/biosíntesis , MicroARNs/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Sitios de Carácter Cuantitativo , ARN Neoplásico/biosíntesis , ARN Neoplásico/genéticaRESUMEN
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain â¼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.
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Mapeo Cromosómico/métodos , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Población Blanca/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , MasculinoRESUMEN
BACKGROUND: Energy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear. OBJECTIVE: We explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association. DESIGN, SETTING, AND PARTICIPANTS: The PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5×10(-3). Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses. RESULTS AND LIMITATIONS: A total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p<0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population. CONCLUSIONS: SNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death. PATIENT SUMMARY: Genetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes.
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Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Metformina/farmacología , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Humanos , Masculino , Estudios Retrospectivos , RiesgoRESUMEN
The 2q37 and 17q12-q22 loci are linked to an increased prostate cancer (PrCa) risk. No candidate gene has been localized at 2q37 and the HOXB13 variant G84E only partially explains the linkage to 17q21-q22 observed in Finland. We screened these regions by targeted DNA sequencing to search for cancer-associated variants. Altogether, four novel susceptibility alleles were identified. Two ZNF652 (17q21.3) variants, rs116890317 and rs79670217, increased the risk of both sporadic and hereditary PrCa (rs116890317: OR = 3.3-7.8, p = 0.003-3.3 × 10(-5) ; rs79670217: OR = 1.6-1.9, p = 0.002-0.009). The HDAC4 (2q37.2) variant rs73000144 (OR = 14.6, p = 0.018) and the EFCAB13 (17q21.3) variant rs118004742 (OR = 1.8, p = 0.048) were overrepresented in patients with familial PrCa. To map the variants within 2q37 and 17q11.2-q22 that may regulate PrCa-associated genes, we combined DNA sequencing results with transcriptome data obtained by RNA sequencing. This expression quantitative trait locus (eQTL) analysis identified 272 single-nucleotide polymorphisms (SNPs) possibly regulating six genes that were differentially expressed between cases and controls. In a modified approach, prefiltered PrCa-associated SNPs were exploited and interestingly, a novel eQTL targeting ZNF652 was identified. The novel variants identified in this study could be utilized for PrCa risk assessment, and they further validate the suggested role of ZNF652 as a PrCa candidate gene. The regulatory regions discovered by eQTL mapping increase our understanding of the relationship between regulation of gene expression and susceptibility to PrCa and provide a valuable starting point for future functional research.
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Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 2/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Variación Genética , Neoplasias de la Próstata/genética , Paseo de Cromosoma , Finlandia , Estudios de Asociación Genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ADN , Análisis de Secuencia de ARNRESUMEN
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
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Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Medición de Riesgo , Factores de RiesgoRESUMEN
Understanding the impact of multiple genetic variants and their interactions on the disease penetrance of familial multiple prostate cancer is very relevant to the overall understanding of carcinogenesis. We assessed the joint effect of two loci on rs4242382 at 8q24 and rs10486567 at 7p15.2 to this end. We analyzed the data from a Finnish family-based genetic study, which was composed of 947 men including 228 cases in 75 families, to evaluate the respective effects of the two loci on the disease penetrance; in particular, the occurrence and number of prostate cancer cases within a family were utilized to evaluate the interactions between the two loci under the additive and multiplicative Poisson regression models. The risk alleles A at rs4242382 (OR = 1.14, 95% CI 1.08-1.19, P<0.0001) and a risk allele A at rs10486567 (OR = 1.06, 96%CI 1.01-1.11, P = 0.0208) were found to be associated with an increased risk of familial PrCa, especially with four or more cases within a family. A multiplicative model fitted the joint effect better than an additive model (likelihood ratio test X(2)â= 13.89, P<0.0001). The influence of the risk allele A at rs10486567 was higher in the presence of the risk allele A at rs4242382 (OR = 1.09 (1.01-1.18) vs. 1.01 (0.95-1.07)). Similar findings were observed in non-aggressive PrCa, but not in aggressive PrCa. We demonstrated that two loci (rs4242382 and rs10486567) are highly associated with familial multiple PrCa, and the gene-gene interaction or statistical epistasis was consistent with the Fisher's multiplicative model. These loci's association and epistasis were observed for non-aggressive but not for aggressive tumors. The proposed statistical model can be further developed to accommodate multi-loci interactions to provide further insights into epistasis.
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Epistasis Genética/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/genética , Alelos , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Riesgo , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Genetic association studies of prostate and other cancers have identified a major risk locus at chromosome 8q24. Several independent risk variants at this locus alter transcriptional regulatory elements, but an affected gene and mechanism for cancer predisposition have remained elusive. The retrogene POU5F1B within the locus has a preserved open reading frame encoding a homolog of the master embryonic stem cell transcription factor Oct4. We find that 8q24 risk alleles are expression quantitative trait loci correlated with reduced expression of POU5F1B in prostate tissue and that predicted deleterious POU5F1B missense variants are also associated with risk of transformation. POU5F1 is known to be self-regulated by the encoded Oct4 transcription factor. We further observe that POU5F1 expression is directly correlated with POU5F1B expression. Our results suggest that a pathway critical to self-renewal of embryonic stem cells may also have a role in the origin of cancer.
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Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Núcleo Celular/metabolismo , Transformación Celular Neoplásica , Bases de Datos Genéticas , Células Madre Embrionarias/citología , Variación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Sistemas de Lectura Abierta , Sitios de Carácter Cuantitativo , Riesgo , Análisis de Secuencia de ADN , Transcripción Genética , Adulto JovenRESUMEN
Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.
Asunto(s)
Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Alelos , Estudios de Casos y Controles , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Linaje , Fenotipo , Factores de RiesgoRESUMEN
Prostate cancer (PCa) is a heterogeneous trait for which several susceptibility loci have been implicated by genome-wide linkage and association studies. The genomic region 13q14 is frequently deleted in tumour tissues of both sporadic and familial PCa patients and is consequently recognised as a possible locus of tumour suppressor gene(s). Deletions of this region have been found in many other cancers. Recently, we showed that homozygous carriers for the T442C variant of the ARLTS1 gene (ADP-ribosylation factor-like tumour suppressor protein 1 or ARL11, located at 13q14) are associated with an increased risk for both unselected and familial PCa. Furthermore, the variant T442C was observed in greater frequency among malignant tissue samples, PCa cell lines and xenografts, supporting its role in PCa tumourigenesis. In this study, 84 PCa cases and 15 controls were analysed for ARLTS1 expression status in blood-derived RNA. A statistically significant (pâ=â0.0037) decrease of ARLTS1 expression in PCa cases was detected. Regulation of ARLTS1 expression was analysed with eQTL (expression quantitative trait loci) methods. Altogether fourteen significant cis-eQTLs affecting the ARLTS1 expression level were found. In addition, epistatic interactions of ARLTS1 genomic variants with genes involved in immune system processes were predicted with the MDR program. In conclusion, this study further supports the role of ARLTS1 as a tumour suppressor gene and reveals that the expression is regulated through variants localised in regulatory regions.
Asunto(s)
Factores de Ribosilacion-ADP/genética , Neoplasias de la Próstata/genética , Anciano , Estudios de Casos y Controles , Finlandia/epidemiología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/metabolismo , Sitios de Carácter Cuantitativo , Factores de RiesgoRESUMEN
BACKGROUND: Chromosomal region 11q13-14 associates with prostate cancer (PrCa). Previously, we identified a rare intronic mutation on EMSY (11q13.5) that increases the risk of aggressive PrCa and associates with familial PrCa. Here, we further study the genetic structure and variants of the PrCa susceptibility region 11q13.5. METHODS: This study included 2716 unselected hospital-based PrCa cases, 1318 cases of a screening trial and 908 controls of Finnish origin. We imputed single nucleotide polymorphisms (SNPs) and structural variants from the 1000 Genomes Project and validated the associations of the variants in two PrCa patient sets by genotyping. Genetic structure was studied with haplotype analysis. RESULTS: Two independent regions at 11q13.5 were associated with PrCa risk. The most significant association was at EMSY (rs10899221, odds ratio (OR) 1.29-1.40, P=3.5 × 10(-4)-0.002) near the previously identified mutation. Correlated intronic SNPs rs10899221 and rs72944758 formed with other EMSY variants common and rare haplotypes that were associated with increased risk (P=4.0 × 10(-4)) and decreased risk (P=0.01) of PrCa, respectively. The other associated region was intergenic. Among the six validated variants, rs12277366 was significant in both patient sets (OR 1.15-1.17, P=0.01). Haplotypes associated with an increased risk (P=0.02) and a decreased risk (P=0.02) were identified. In addition, the intergenic region was strongly associated with PrCa death, with the most significant association at rs12277366 (OR=0.72, P=4.8 × 10(-5)). CONCLUSIONS: These findings indicate that 11q13.5 contributes to PrCa predisposition with complex genetic structure and is associated with PrCa death.
Asunto(s)
Cromosomas Humanos Par 11 , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Finlandia/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/mortalidad , Factores de RiesgoRESUMEN
BACKGROUND: A recently identified germline mutation G84E in HOXB13 was shown to increase the risk of prostate cancer. In a family-based analysis by The International Consortium for Prostate Cancer Genetics (ICPCG), the G84E mutation was most prevalent in families from the Nordic countries of Finland (22.4%) and Sweden (8.2%). METHODS: To further investigate the importance of G84E in the Finns, we determined its frequency in more than 4,000 prostate cancer cases and 5,000 controls. In addition, 986 breast cancer and 442 colorectal cancer (CRC) cases were studied. Genotyping was conducted using TaqMan, MassARRAY iPLEX, and sequencing. Statistical analyses were conducted using Fisher exact test, and overall survival was analyzed using Cox modeling. RESULTS: The frequency of the G84E mutation was significantly higher among patients with prostate cancer and highest among patients with a family history of the disease, hereditary prostate cancer [8.4% vs. 1.0% in controls; OR 8.8; 95% confidence interval (CI), 4.9-15.7]. The mutation contributed significantly to younger age (≤55 years) at onset and high prostate-specific antigen (PSA; ≥20 ng/mL) at diagnosis. An association with increased prostate cancer risk in patients with prior benign prostate hyperplasia (BPH) diagnosis was also revealed. No statistically significant evidence for a contribution in CRC risk was detected, but a suggestive role for the mutation was observed in familial BRCA1/2-negative breast cancer. CONCLUSIONS: These findings confirm an increased cancer risk associated with the G84E mutation in the Finnish population, particularly for early-onset prostate cancer and cases with substantially elevated PSA. IMPACT: This study confirms the overall importance of the HOXB13 G84E mutation in prostate cancer susceptibility.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/etiología , Neoplasias Colorrectales/etiología , Proteínas de Homeodominio/genética , Mutación/genética , Polimorfismo Genético/genética , Neoplasias de la Próstata/etiología , Adolescente , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/mortalidad , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/mortalidad , ADN/genética , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/mortalidad , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.