RESUMO
Polygenic risk scores (PRSs) calculated from genome-wide association studies (GWASs) of non-melanoma skin cancer (NMSC) in a general, non-transplant setting have recently been shown to predict risk of and time to post-renal transplant skin cancer. In this study, we set out to test these findings in a cohort of heart, lung, and liver transplant patients to see whether these scores could be applied across different organ transplant types. Using the PRS from Stapleton et al (2018), PRS was calculated for each sample across a European ancestry heart, lung, and liver transplant cohorts (n = 523) and tested as predictor of time to NMSC post-transplant. The top PRS, squamous cell carcinoma (SCC) pT1 x 10-5 , (n SNPs = 1953), SCC pT1 x 10-6 , and SCC pT1 x 10-6 (n SNPs = 1061) were significantly predictive in the time to NMSC, SCC, and basal cell carcinoma (BCC) analysis across organ (P = .006, .02, and .02, respectively). We observed here a similar direction of effect and effect size [NMSC HR = 1.31(1.08-1.59)] to that in the original discovery study with increased polygenic burden leading to a faster time to developing NMSC. In summary, we found that PRS of NMSC calculated from GWAS of NMSC in non-transplant populations independently replicated in this cohort of heart, lung, and liver transplant.
Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Estudo de Associação Genômica Ampla , Humanos , Incidência , Fatores de Risco , Neoplasias Cutâneas/genéticaRESUMO
The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT-03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n = 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n = 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non-ACR (area under the receiver operating characteristic curve = 90%, 95% confidence interval = 82%-96%) and predicted ACR events up to 40 days before biopsy-proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection-associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death-related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. CONCLUSION: Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection-associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune-mediated damage to the allograft. (Hepatology 2017;65:269-280).
Assuntos
Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Transplante de Fígado , MicroRNAs/sangue , Expressão Ectópica do Gene , Feminino , Rejeição de Enxerto/genética , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Transcriptoma , Transplante HomólogoRESUMO
OBJECTIVE: To validate six previously identified markers among men at increased risk of prostate cancer (African-American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study. PATIENTS AND METHODS: Eligibility criteria for PRAP include age 35-69 years with a family history of prostate cancer, African-American ethnicity regardless of family history, and known BRCA gene mutations. The genome-wide association study markers assessed included rs2736098 (5p15.33), rs10993994 (10q11), rs10788160 (10q26), rs11067228 (12q24), rs4430796 (17q12) and rs17632542 (19q13.33). Genotyping methods included either the Taqman(®) single nucleotide polymorphism (SNP) genotyping assay (Applied Biosystems, Foster City, CA, USA) or pyrosequencing. Linear regression models were used to evaluate the association between individual markers and log-transformed baseline PSA levels, while adjusting for potential confounders. RESULTS: A total of 707 participants (37% Caucasian, 63% African-American) with clinical and genotype data were included in the analysis. Rs10788160 (10q26) was strongly associated with PSA levels among Caucasian participants in the high-risk group (P < 0.01), with a 33.2% increase in PSA level with each A-allele carried. Furthermore, rs10993994 (10q11) was found to be associated with PSA level (P = 0.03) in Caucasian men in the high-risk group, with a 15% increase in PSA level with each T-allele carried. A PSA adjustment model based on allele carrier status at rs10788160 and rs10993994 was proposed, specific to high-risk Caucasian men. CONCLUSIONS: Genetic variation at 10q may be particularly important in personalizing the interpretation of PSA level for Caucasian men in the high-risk group. Such information may have clinical relevance in shared decision-making and individualized prostate cancer screening strategies for Caucasian men in the high-risk group, although further study is warranted.
Assuntos
Estudo de Associação Genômica Ampla , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Adulto , Idoso , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , População BrancaRESUMO
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.
Assuntos
Variação Genética , Mutação , Neoplasias da Próstata/genética , Receptores Imunológicos/genética , Idoso , Substituição de Aminoácidos , População Negra/genética , Análise Mutacional de DNA , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Neoplasias da Próstata/etiologia , Estrutura Terciária de Proteína , Receptores Imunológicos/metabolismo , Receptores Depuradores , Receptores Depuradores Classe A , População Branca/genéticaRESUMO
A single nucleotide polymorphism (SNP) at 10q11 (rs10993994) in the 5' region of the MSMB gene was recently implicated in prostate cancer risk in two genome-wide association studies. To identify possible causal variants in the region, we genotyped 16 tagging SNPs and imputed 29 additional SNPs in approximately 65 kb genomic region at 10q11 in a Swedish population-based case-control study (CAncer of the Prostate in Sweden), including 2899 cases and 1722 controls. We found evidence for two independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP rs10993994 was most significant. Importantly, using an MSMB promoter reporter assay, we showed that the risk allele of this SNP had only 13% of the promoter activity of the wild-type allele in a prostate cancer model, LNCaP cells. Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells. However, its association was only weakly confirmed in one of the three additional study populations. The observations that rs10993994 is the strongest associated variant in the region and its risk allele has a major effect on the transcriptional activity of MSMB, a gene with previously described prostate cancer suppressor function, together suggest the T allele of rs10993994 as a potential causal variant at 10q11 that confers increased risk of prostate cancer.
Assuntos
Cromossomos Humanos Par 10/genética , Predisposição Genética para Doença , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Proteínas Secretadas pela Próstata/genética , Androgênios/farmacologia , Sequência de Bases , Humanos , Masculino , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , SuéciaRESUMO
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in five chromosomal regions--three at 8q24 and one each at 17q12 and 17q24.3--have been associated with prostate cancer. Each SNP has only a moderate association, but when SNPs are combined, the association may be stronger. METHODS: We evaluated 16 SNPs from five chromosomal regions in a Swedish population (2893 subjects with prostate cancer and 1781 control subjects) and assessed the individual and combined association of the SNPs with prostate cancer. RESULTS: Multiple SNPs in each of the five regions were associated with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in a multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men we studied. The five SNPs plus family history had a cumulative association with prostate cancer (P for trend, 3.93x10(-28)). In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46 (P=1.29x10(-8)), as compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis. CONCLUSIONS: SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer.
Assuntos
Cromossomos Humanos Par 17 , Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Genótipo , Humanos , Modelos Logísticos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , RiscoRESUMO
PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.
Assuntos
Saúde da Família , Antígeno Prostático Específico/análise , Neoplasias da Próstata/genética , Idoso , Área Sob a Curva , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Curva ROC , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Lipoprotein lipase (LPL) is in chromosome 8p22, site of one of the most common somatic deletions in prostate tumors. Additionally, a CpG island (CGI) was identified in the LPL promoter region. To test the hypothesis that LPL is a tumor suppressor gene, which is inactivated by somatic deletion and hypermethylation in prostate cancer, we evaluated somatic DNA deletion and methylation status at LPL in 56 pairs of DNA samples isolated from prostate cancer tissues and matching normal controls and 11 prostate cell lines. We found that the DNA in 21 of 56 primary cancers (38%) was methylated in the LPL promoter CGI, whereas no methylation was detected in any normal samples. In addition, we found a hemizygous deletion at LPL in 38 of the 56 tumors (68%). When the results of deletion and methylation were considered together, we found LPL promoter CGI methylation occurred in 45% of LPL deleted tumors and in 22% of LPL retained tumors. Within several clinical characteristics tested, the preoperative PSA levels were found to be significantly higher in subjects with LPL promoter CGI methylation compared with subjects without LPL promoter methylation (p=0.0012). Additionally, demethylation of the LPL promoter CGI was accompanied by transcriptional reactivation of LPL in the prostate cancer cell lines DU145 and PC3. In summary, we report a novel finding that the LPL gene is commonly methylated in prostate tumors, and our results suggest that biallelic inactivation of LPL by chromosomal deletion and promoter hypermethylation may play a role in human prostate cancer.
Assuntos
Deleção Cromossômica , Epigênese Genética , Genes Supressores de Tumor , Lipase Lipoproteica/genética , Neoplasias da Próstata/genética , Ilhas de CpG , Metilação de DNA , Humanos , Masculino , Regiões Promotoras Genéticas , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated. METHODS: Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2'-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR. RESULTS: We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3. CONCLUSION: We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development.
Assuntos
Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/fisiopatologia , Linhagem Celular Tumoral , Deleção Cromossômica , Ilhas de CpG/fisiologia , Metilação de DNA , Proteínas Ligadas por GPI , Humanos , Masculino , Regiões Promotoras Genéticas/fisiologia , Membro 10c de Receptores do Fator de Necrose Tumoral , Receptores Chamariz do Fator de Necrose Tumoral/genéticaRESUMO
BACKGROUND: Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS: We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS: Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P < or = 0.05) were found for six SNPs. These six SNPs had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS: Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening.
Assuntos
Frequência do Gene/genética , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Humanos , Masculino , Análise Multivariada , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Sistema de Registros , Fatores de Risco , SuéciaRESUMO
PURPOSE: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. EXPERIMENTAL DESIGN: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. RESULTS: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. CONCLUSIONS: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.
Assuntos
Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Idoso , Biomarcadores Tumorais , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Fatores de RiscoRESUMO
The evidence for tumor suppressor genes at 8p is well supported by many somatic deletion studies and genetic linkage studies. However, it remains a challenge to pinpoint the tumor suppressor genes at 8p primarily because the implicated regions are broad. In this study, we attempted to narrow down the implicated regions by incorporating evidence from both somatic and germline studies. Using high-resolution Affymetrix arrays, we identified two small common deleted regions among 55 prostate tumors at 8p23.1 (9.8-11.5 Mb) and 8p21.3 (20.6-23.7 Mb). Interestingly, our fine mapping linkage analysis at 8p among 206 hereditary prostate cancer families also provided evidence for linkage at these two regions at 8p23.1 (5.8-11.2 Mb) and at 8p21.3 (19.6-23.9 Mb). More importantly, by combining the results from the somatic deletion analysis and genetic linkage analysis, we were able to further narrow the regions to approximately 1.4 Mb at 8p23.1 and approximately 3.1 Mb at 8p21.3. These smaller consensus regions may facilitate a more effective search for prostate cancer genes at 8p.
Assuntos
Cromossomos Humanos Par 8/genética , Sequência Consenso , Deleção de Genes , Ligação Genética , Neoplasias da Próstata/genética , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: A strong cumulative effect of five genetic variants and family history on prostate cancer risk was recently reported in a Swedish population (CAPS). We carried out this study to confirm the finding in two U.S. study populations and perform a combined analysis to obtain a more stable estimate of the odds ratio (OR) for prostate cancer. METHODS: We evaluated three SNPs at 8q24 and one SNP each at 17q12 and 17q24.3 in two study populations in the U.S. The first was a hospital-based case-control study population at Johns Hopkins Hospital (JHH), including 1,563 prostate cancer patients and 576 control subjects. The second was the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, including 1,172 prostate cancer patients and 1,157 control subjects. RESULTS: We confirmed a cumulative effect of five risk variants on prostate cancer risk. Based on a total of 5,628 cases and 3,514 controls from JHH, CGEMS, and CAPS, men who carry any combination of 1, 2, 3, and 4 or more of these five risk variants have an estimated OR (95% CI) of 1.41 (1.20-1.67), 1.88 (1.59-2.22), 2.36 (1.95-2.85), and 3.80 (2.77-5.22) for prostate cancer, respectively, compared to men who do not have any of these five risk variants. When family history was included, the cumulative effect was stronger. DISCUSSION: These results provide an important confirmation for the cumulative effect of five genetic risk variants on prostate cancer risk. The more stable OR estimates of the cumulative effect of these six risk factors are a major step toward individual risk characterization for this disease.
Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Neoplasias da Próstata/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Over the past 2 decades, DNA samples from thousands of families have been collected and genotyped for linkage studies of common complex diseases, such as type 2 diabetes, asthma, and prostate cancer. Unfortunately, little success has been achieved in identifying genetic susceptibility risk factors through these considerable efforts. However, significant success in identifying common disease risk-associated variants has been recently achieved from genome-wide association studies using unrelated case-control samples. These genome-wide association studies are typically done using population-based cases and controls that are ascertained irrespective of their family history for the disease of interest. Few genetic association studies have taken full advantage of the considerable resources that are available from the linkage-based family collections despite evidence showing cases that have a positive family history of disease are more likely to carry common genetic variants associated with disease susceptibility. Herein, we argue that population stratification is still a concern in case-control genetic association studies, despite the development of analytic methods designed to account for this source of confounding, for a subset of single nucleotide polymorphisms in the genome, most notably those single nucleotide polymorphisms in regions involved with natural selection. We note that current analytic approaches designed to address the issue of population stratification in case-control studies cannot definitively distinguish between true and false associations, and we argue that family-based samples can still serve an invaluable role in following up findings from case-control studies.
Assuntos
Saúde da Família , Ligação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Alelos , Frequência do Gene/genética , Genoma Humano , Humanos , Modelos GenéticosRESUMO
PURPOSE: Chromosome 6q14-21 is commonly deleted in prostate cancers, occurring in approximately 22% of all tumors and approximately 40% of metastatic tumors. However, candidate prostate tumor suppressor genes in this region have not been identified, in part due to the large and broad nature of the deleted region implicated in previous studies. EXPERIMENTAL DESIGN: We first used high-resolution Affymetrix single nucleotide polymorphism arrays to examine DNA from malignant and matched nonmalignant cells from 55 prostate cancer patients. We identified a small consensus region on 6q14-21 and evaluated the deletion status within the region among additional 40 tumors and normal pairs using quantitative PCR and fluorescence in situ hybridization. We finally tested the association between the deletion and Gleason score using the Fisher's exact test. RESULTS: Tumors with small, interstitial deletions at 6q14-21 defined an 817-kb consensus region that is affected in 20 of 21 tumors. The MAP3K7 gene is one of five genes located in this region. In total, MAP3K7 was deleted in 32% of 95 tumors. Importantly, deletion of MAP3K7 was highly associated with higher-grade disease, occurring in 61% of tumors with Gleason score >or=8 compared with only 22% of tumors with Gleason score Assuntos
Deleção Cromossômica
, Cromossomos Humanos Par 6
, Deleção de Genes
, MAP Quinase Quinase Quinases/genética
, Neoplasias da Próstata/genética
, Humanos
, MAP Quinase Quinase Quinases/análise
, Masculino
, Polimorfismo de Nucleotídeo Único
, Neoplasias da Próstata/patologia
RESUMO
NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper.
Assuntos
Mutação em Linhagem Germinativa , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Segregação de Cromossomos , Cromossomos Humanos Par 8/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ligação Genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Neoplasias da Próstata/metabolismo , Estrutura Terciária de Proteína , RNA Mensageiro/genética , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.
Assuntos
Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Alelos , Processamento Alternativo , Sítios de Ligação , Proteínas de Ciclo Celular/antagonistas & inibidores , Processos de Crescimento Celular/genética , Inibidor de Quinase Dependente de Ciclina p21 , Genes Supressores de Tumor , Humanos , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Isoformas de Proteínas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas de Ligação a RNA , Fatores de Processamento de Serina-Arginina , Transativadores/antagonistas & inibidores , Transativadores/biossíntese , TransfecçãoRESUMO
Chronic or recurrent inflammation has been suggested as a causal factor in several human malignancies, including prostate cancer. Genetic predisposition is also a strong risk factor in the development of prostate cancer. In particular, Toll-like receptors (TLR), especially the TLR6-1-10 gene cluster, are involved in prostate cancer development. Interleukin-1 receptor-associated kinases (IRAK) 1 and 4 are critical components in the TLR signaling pathway. In this large case-control study, we tested two hypotheses: (a) sequence variants in IRAK1 and IRAK4 are associated with prostate cancer risk and (b) sequence variants in IRAK1/4 and TLR1-6-10 interacts and confers a stronger risk to prostate cancer. We analyzed 11 single nucleotide polymorphisms (four in IRAK1 and seven in IRAK4) among 1,383 newly diagnosed prostate cancer patients and 780 population controls in Sweden. Although the single-nucleotide polymorphisms in IRAK1 and IRAK4 alone were not significantly associated with prostate cancer risk, one single-nucleotide polymorphism in IRAK4, when combined with the high-risk genotype at TLR6-1-10, conferred a significant excess risk of prostate cancer. In particular, men with the risk genotype at TLR6-1-10 and IRAK4-7987 CG/CC had an odds ratio of 9.68 (P = 0.03) when compared with men who had wild-type genotypes. Our findings suggest synergistic effects between sequence variants in IRAK4 and the TLR 6-1-10 gene cluster. Although this study was based on a priori hypothesis and was designed to address many common issues facing this type of study, our results need confirmation in even larger studies.
Assuntos
Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias da Próstata/genética , Receptores de Interleucina-1/genética , Receptores Toll-Like/genética , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Seguimentos , Frequência do Gene , Variação Genética , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Família Multigênica , Neoplasias da Próstata/epidemiologia , Valores de Referência , Medição de Risco , Suécia/epidemiologia , Receptor 1 Toll-Like/genética , Receptor 10 Toll-Like/genética , Receptor 6 Toll-Like/genéticaRESUMO
The loss of cell cycle control is believed to be an important mechanism in the promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and functions as an important cell cycle gatekeeper. Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology. In addition, a case-control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is associated with advanced prostate cancer. In light of the evidence for linkage between the chromosomal location of the CDKN1B gene (12p13) and prostate cancer susceptibility in several hereditary prostate cancer (HPC) populations, we hypothesized that sequence variants of CDKN1B play a role in HPC. To test this hypothesis, we first resequenced this gene in 96 HPC probands to identify germ-line mutations and sequence variants. We then genotyped the identified sequence variants among all family members of 188 HPC families and tested for their cosegregation with prostate cancer. In total, 10 sequence variants were identified, including three nonsynonymous changes. A family-based test, which is free from the effects of population stratification, revealed a significant association between single nucleotide polymorphism (SNP) -79C/T and prostate cancer (with a nominal P of 0.0005). The C allele of -79C/T was overtransmitted from parents to their affected offspring. Evidence for this association was primarily contributed by affected offspring whose age at diagnosis was <65 years. Together with the previous association study in a sporadic prostate cancer population, our new findings additionally suggest that germ-line variants of this gene play a role in prostate cancer susceptibility.
Assuntos
Proteínas de Ciclo Celular/genética , Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/genética , Idoso , Inibidor de Quinase Dependente de Ciclina p27 , Saúde da Família , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores de RiscoRESUMO
Long-term estrogen exposure and family history of breast cancer are the two factors that are most consistently found to be associated with breast cancer risk. Sequence variants in genes involved in estrogen synthesis, metabolism, and signal transduction may account, in part, for this observation. Using data and DNA samples from the Shanghai Breast Cancer Study, we tested the hypothesis that sequence variants of the estrogen receptor beta gene (ESR2) may be associated with increased risk for breast cancer, particularly among women who have a high level and long-term endogenous estrogen exposure. Direct sequencing of the ESR2 gene among 30 Chinese women revealed eight sequence variants. Association analysis of six common sequence variants in 1134 cases and 1235 controls provided evidence for positive associations between breast cancer risk and two single nucleotide polymorphisms (SNPs), [C(14206)T and C(33390)G], among postmenopausal women. Evidence of a stronger association was found for SNP [C(33390)G] among women with a long duration (> or =34 years) of menstruation (odds ratio, 2.37; 95% confidence interval, 1.18-4.77). A potential synergistic effect between SNP [C(33390)G] and several steroid sex hormones was observed, and a 3-4-fold elevated risk of breast cancer was found among women with a CG or GG genotype in SNP [C(33390)G] combined with a high level of steroid sex hormone or a low level of sex hormone binding globulin. Our results are consistent with the hypothesis of a joint effect of estrogen receptor beta sequence variants and endogenous estrogen exposure on breast cancer risk.