RESUMO
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.
Assuntos
Arginina/genética , Endorribonucleases/genética , Predisposição Genética para Doença , Mutação Puntual , Neoplasias da Próstata/genética , Idoso , Substituição de Aminoácidos , Estudos de Casos e Controles , Análise Mutacional de DNA , Deleção de Genes , Dosagem de Genes , Mutação em Linhagem Germinativa , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/epidemiologiaRESUMO
Silencing of hMLH1 expression by aberrant hMLH1 promoter methylation accounts for the majority of sporadic colon cancers with microsatellite instability. We have previously shown hMLH1 silencing is biallelic and actively maintained. To study the mechanism of aberrant hMLH1 methylation, we assayed whether an hMLH1 methylated cell could transfer methylation and silencing to an exogenous hMLH1 promoter in somatic cell hybrids between hMLH1 methylated-silenced and hMLH1 unmethylated-expressing colon cancer cells. Conversely, we assayed whether these hybrids could reactivate expression of initially methylated and silenced hMLH1 alleles. Compellingly, within the hybrids each hMLH1 allele remained unchanged, retaining the expression status of its parental cell of origin. This chromosomal autonomy may not be simply determined by DNA methylation, as it is reasserted after experimentally forced demethylation of all hMLH1 alleles in the hybrids. Confirming findings included hMLH1 methylated cells being unable to methylate single transferred exogenous hMLH1 expressing chromosomes or transfected hMLH1 reporter constructs. hMLH1 silencing does not conform to either a dominant or recessive model, and is not determined by trans-acting factors differing between hMLH1 expressing or silenced genomes. We posit that hMLH1 methylation is dependent on and maintained by cis chromosomal marks, whose nature remains to be elucidated.
Assuntos
Cromossomos Humanos Par 3/genética , Neoplasias do Colo/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Azacitidina/farmacologia , Western Blotting , Proteínas de Transporte , Cromossomos Humanos Par 3/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Genes Reporter/genética , Humanos , Células Híbridas/metabolismo , Proteína 1 Homóloga a MutL , Proteínas Nucleares , Plasmídeos/genética , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasAssuntos
Proteínas Morfogenéticas Ósseas/genética , Predisposição Genética para Doença , Proteína Antagonista do Receptor de Interleucina 1/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Fator 15 de Diferenciação de Crescimento , Humanos , Masculino , Fatores de RiscoRESUMO
The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSI-H)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex.
Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Instabilidade de Microssatélites , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Feminino , Estudos de Associação Genética , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Fenótipo , Garantia da Qualidade dos Cuidados de Saúde , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores Sexuais , Adulto JovemRESUMO
We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer [odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09-4.20, P=0.03] and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23-5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01-9.15) and OR=4.42 for two deletions (95%CI=1.32-14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02-2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.
Assuntos
Predisposição Genética para Doença , Variação Genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Sialoglicoproteínas/genética , Negro ou Afro-Americano/genética , Desequilíbrio Alélico , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 7 , Intervalos de Confiança , Análise Mutacional de DNA , DNA de Neoplasias , Éxons , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Mutação de Sentido Incorreto , Invasividade Neoplásica , Estadiamento de Neoplasias , Técnicas de Amplificação de Ácido Nucleico , Razão de Chances , Antígeno Prostático Específico/sangue , Estudos Retrospectivos , Risco , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
According to recently published guidelines, microsatellite instability (MSI) testing of colorectal cancers may be clinically indicated on a significant proportion of all colorectal tumors. To date, nothing has been published regarding the reproducibility of MSI testing between laboratories. We present MSI quality control activities experience of a six center multinational consortium, as laboratories developed competency with MSI testing and interpretation. The aim of this paper is to share lessons learned and to describe the final concordance rates in scoring MSI markers within this consortium.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Humanos , Controle de Qualidade , Sistema de RegistrosRESUMO
Whole-genome scan studies recently identified a locus on chromosome segments 19q12-q13.11 linked to prostate tumor aggressiveness by use of the Gleason score as a quantitative trait. We have now completed finer-scale linkage mapping across this region that confirmed and narrowed the candidate region to 2 cM, with a peak between markers D19S875 and D19S433. We also performed allelic imbalance (AI) studies across this region in primary prostate tumors from 52 patients unselected for family history or disease status. A high level of AI was observed, with the highest rates at markers D19S875 (56%) and D19S433 (60%). Furthermore, these two markers defined a smallest common region of AI of 0.8 Mb, with 15 (29%) prostate tumors displaying interstitial AI involving one or both markers. In addition, we noted a positive association between AI at marker D19S875 and extension of tumor beyond the margin (P = 0.02) as well as a higher Gleason score (P = 0.06). These data provide strong evidence that we have mapped a prostate tumor aggressiveness locus to chromosome segments 19q12-q13.11 that may play a role in both familial and non-familial forms of prostate cancer.