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Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R2 > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years, p < 0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC > 0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases.
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Neoplasias de la Mama/genética , Reparación del ADN , Recombinasas/genética , Adulto , Factores de Edad , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Roturas del ADN de Doble Cadena , Femenino , Frecuencia de los Genes , Alemania/epidemiología , Haplotipos , Humanos , Persona de Mediana Edad , PenetranciaRESUMEN
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
BACKGROUND: In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS: In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS: Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS: These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.
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Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 8/genética , Estudio de Asociación del Genoma Completo , Cooperación Internacional , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/genética , Anciano , Interpretación Estadística de Datos , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
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Cromosomas Humanos X , Neoplasias de la Próstata/genética , Alelos , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Repeticiones de MicrosatéliteRESUMEN
The scoring of micronuclei (MN) is widely used in biomonitoring and mutagenicity testing as a surrogate marker of chromosomal damage inflicted by clastogenic agents or by aneugens. Individual differences in the response to a mutagenic challenge are known from studies on cancer patients and carriers of mutations in DNA repair genes. However, it has not been studied to which extent genetic factors contribute to the observed variability of individual MN frequencies. Our aim was to quantify this heritable genetic component of both baseline and radiation-induced MN frequencies. We performed a twin study comprising 39 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs. Due to the small number of DZ pairs, we had to recruit controls from which 38 age- and gender-matched random control pairs (CPs) were generated. For heritability estimates, we used biometrical modelling of additive genetic, common environmental, and unique environmental components (ACE model) of variance and direct comparison of variance between the sample groups. While heritability estimates from MZ to DZ comparisons produced inconclusive results, both estimation methods revealed a high degree of heritability (h(2)) for baseline MN frequency (h(2) = 0.68 and h(2) = 0.72) as well as for the induced frequency (h(2) = 0.68 and h(2) = 0.57) when MZ were compared to CP. The result was supported by the different intraclass correlation coefficients of MZ, DZ and CP for baseline (r = 0.63, r = 0.31 and r = 0.0, respectively) as well as for induced MN frequencies (r = 0.79, r = 0.74 and r = 0.0, respectively). This study clearly demonstrates that MN frequencies are determined by genetic factors to a major part. The strong reflection of the genetic background supports the idea that MN frequencies represent an intermediate phenotype between molecular DNA repair mechanisms and the cancer phenotype and affirms the approaches that are made to utilise them as predictors of, for example, cancer risk.
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Predisposición Genética a la Enfermedad , Micronúcleos con Defecto Cromosómico , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adolescente , Adulto , Femenino , Humanos , Masculino , Pruebas de Micronúcleos , Mutágenos/toxicidad , Tolerancia a Radiación/genética , Adulto JovenRESUMEN
Leptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.
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BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.
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Neoplasias de la Próstata , Genes BRCA2 , Factores de Intercambio de Guanina Nucleótido , Humanos , Masculino , Clasificación del Tumor , Neoplasias de la Próstata/genética , Proteínas Serina-Treonina Quinasas , Tripsina , Secuenciación del ExomaRESUMEN
BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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Predisposición Genética a la Enfermedad , Neoplasias de la Próstata , Proteínas de la Ataxia Telangiectasia Mutada/genética , Mutación de Línea Germinal , Humanos , Masculino , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genéticaRESUMEN
BACKGROUND: Association between genetic variants located on human chromosome 8q24.21 with an increased risk for prostatic carcinoma has been well established. POU5F1P1, a processed pseudogene homologous to the pluripotency factor OCT4, is the only sequence with coding capacity in this region. The objective of this study was to investigate the POU5F1P1 expression in prostatic carcinoma and carcinoma surrounding prostatic tissue. METHODS: RT-PCR and real-time PCR was used to measure the expression of POU5F1P1 relative to the expression of HPRT1 in cell lines, prostatic carcinoma and carcinoma surrounding prostatic tissue. The structure of the POU5F1P1 mRNA and the promoter sequence were elucidated by 5'-RACE experiments. The POU5F1P1 protein was shown with immunohistochemistry on prostate tissue. RESULTS: POU5F1P1 was found to be the only member of the POU5F1 family to be expressed in prostate with over-expression in prostatic carcinoma compared to surrounding prostatic tissue probably because of an increased density of expressing cells. The POU5F1P1 expression is driven by a variety of promoter structures scattered over a genomic region of 860 kB. CONCLUSIONS: The over-expression of POU5F1P1 in prostatic carcinoma in addition to its genomic location and the putative function of its gene product render POU5F1P1 a good candidate to harbour functional genetic variants which modulate prostatic cancer susceptibility.
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Adenocarcinoma/genética , Predisposición Genética a la Enfermedad/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Neoplasias de la Próstata/genética , Adenocarcinoma/metabolismo , Anciano , Línea Celular Tumoral , Cromosomas Humanos Par 8/genética , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Regiones Promotoras Genéticas/genética , Neoplasias de la Próstata/metabolismoRESUMEN
(1) Background: Genetically based hyperinflammation may play a role in pathogen defense. We here questioned whether alterations in circulating monocytes/macrophages, inflammatory biomarkers and a functional SNP (single nucleotide polymorphisms) of the Interleukin-6 (IL-6) promotor might play a role in patients with persistent, and treatment resistant borreliosis. (2) Methods: Leukocyte subpopulations were studied by flow cytometry; plasma cytokines were determined by a chemiluminescence based ELISA (Immulite®), and genotypes of the IL-6 promotor SNP rs1800795 were determined by pyrosequencing. (3) Results: In a cohort of n = 107 Lyme borreliosis patients, who concomitantly manifested either malignant diseases (group 1), autoimmune disorders (group 2), neurological diseases (group 3), or morbidities caused by multiple other infectious complications (group 4), we found decreased numbers of anti-inflammatory CD163-positive macrophages, elevated concentrations of inflammatory cytokines, and an imbalance of IL-6 promotor SNP rs1800795 genotypes. The most prominently upregulated cytokines were IL-1ß, and IL-8. (4) Conclusions: Increased pro-inflammatory phenotypes identified by monocyte/macrophage subtypes and concomitantly increased cytokines appear to be valid to monitor disease activity in patients with persistent Lyme borreliosis. Patterns may vary by additional co-morbidities. In patients with autoimmune diseases, increased frequencies of a heterozygous IL-6 promotor SNP rs1800795 were identified. This functional SNP may guide chronic inflammation, impacting other cytokines to trigger trigger chronicity and therapeutic resistance in Lyme borreliosis.
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The human genome is composed of long stretches of DNA with distinct GC contents, called isochores or GC-content domains. A boundary between two GC-content domains in the human NF1 gene region is also a boundary between domains of early- and late-replicating sequences and of regions with high and low recombination frequencies. The perfect conservation of the GC-content distribution in this region between human and mouse demonstrates that GC-content stabilizing forces must act regionally on a fine scale at this locus. To further elucidate the nature of these forces, we report here on the spectrum of human SNPs and base pair substitutions between human and chimpanzee. The results show that the mutation rate changes exactly at the GC-content transition zone from low values in the GC-poor sequences to high values in GC-rich ones. The GC content of the GC-poor sequences can be explained by a bias in favor of GC > AT mutations, whereas the GC content of the GC-rich segment may result from a fixation bias in favor of AT > GC substitutions. This fixation bias may be explained by direct selection by the GC content or by biased gene conversion.
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Composición de Base , Evolución Molecular , Genoma , Isocoras/genética , Neurofibromina 1/genética , Animales , Emparejamiento Base , Humanos , Pan troglodytes/genética , Polimorfismo de Nucleótido Simple , Recombinación GenéticaRESUMEN
The chromosomal region 7q was repeatedly found to be rearranged in prostate carcinoma. It harbors several well described candidate tumor suppressor and oncogenes. We addressed two genes with opposite roles in cancer; CAV1, a putative tumor suppressor gene at 7q31, and EZH2 at 7q36, which is believed to promote tumor progression. Our primary aim was to assess their expression changes in primary tumors, and then to elucidate the underlying mechanism, assuming that genomic alterations of either locus could affect the other gene as well. In 35 prostate tumor samples, compared with adjacent tissues, CAV1 was overall downregulated (P < 10(-06)), whereas EZH2 was significantly overexpressed (P < 10(-06)). The observed dysregulations were coincident in nearly 70% of the cases. Copy number changes occurred in few tumors. Loss of CAV1 DNA was only marginally associated with reduced expression (P = 0.07), however, and genomic amplification of EZH2 could not explain its upregulation. Through bisulfite sequencing of four tumor samples, CpG-hypermethylation was verified as an alternative mechanism for CAV1 silencing, as reported previously. Moreover, it could also be involved in the reactivation of EZH2.
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Caveolina 1/genética , Cromosomas Humanos Par 7/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Factores de Transcripción/genética , Islas de CpG , Metilación de ADN , Cartilla de ADN , Proteína Potenciadora del Homólogo Zeste 2 , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Complejo Represivo Polycomb 2 , Neoplasias de la Próstata/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Supported by different investigations, multi-step models for tumorigenesis have been proposed for epithelial tumors. The age specific incidence of some cancers shows an exponential rise with increasing patient age. Yet, the onset and the slope of incidence curves varies between tumor types. One simple explanation for this disparity is that the number of mutations required for transformation differs in various tissues. We used a homogeneous Poisson process to estimate the number of events (N) and the intensity or event rate (lambda) that might be needed for cancer development in various tissues (colon, prostate, oralpharynx, larynx). Estimations were performed, including 95% confidence intervals, for the male and female population. The expected number of events needed was higher in adenocarcinomas (colorectal carcinoma: N approximately 10 for females and N approximately 11.0 for males; prostatic cancer: N approximately 23) than in squamous cell carcinomas (oropharynx: N approximately 5-6 for females and N approximately 6 for males; larynx: N approximately 7 for females and N approximately 8 males). Still, alternative models fixing N to values within the 95% confidence intervals determined, showed good coincidence with epidemiological data. Although the herein applied mathematical model neglects several biologic conditions, especially a presumed acceleration of mutation rates after tumor initiation it offers a plausible theory for the given epidemiologic data and matches with molecular biologic findings in the investigated cancers.
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Mutación , Neoplasias/epidemiología , Neoplasias/genética , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Adolescente , Adulto , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Simulación por Computador , Intervalos de Confianza , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Laríngeas/epidemiología , Neoplasias Laríngeas/genética , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Estadificación de Neoplasias , Neoplasias Orofaríngeas/epidemiología , Neoplasias Orofaríngeas/genética , Distribución de Poisson , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery. METHODS: In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis. RESULTS: Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the codon 634 genotype. No lymph-node metastases were noted in patients younger than 14 years of age. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation. CONCLUSIONS: These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.
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Carcinoma Medular/genética , Mutación Puntual , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Neoplasias de la Tiroides/genética , Adolescente , Factores de Edad , Carcinoma Medular/fisiopatología , Carcinoma Medular/prevención & control , Niño , Codón/genética , Progresión de la Enfermedad , Femenino , Mutación de Línea Germinal , Humanos , Hiperplasia , Escisión del Ganglio Linfático , Masculino , Estadificación de Neoplasias , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret , Riesgo , Encuestas y Cuestionarios , Glándula Tiroides/patología , Glándula Tiroides/cirugía , Neoplasias de la Tiroides/fisiopatología , Neoplasias de la Tiroides/prevención & control , TiroidectomíaRESUMEN
Expression of p16 has been established as a good surrogate marker for high-risk human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) patients, and it has been associated with an improved prognosis, irrespective of the actual HPV status. Conversely, the human insulin-like growth factor II mRNA binding protein 3 (IMP3) has been related to aggressiveness in several types of tumors. The aim of the present study was to investigate and compare p16 and IMP3 as markers of favorable and unfavorable behavior, respectively, in head and neck SCC (HNSCC), with particular reference to the HPV status. Both markers were analyzed by immunohistochemical analysis of 156 HNSCC samples originating from the oropharynx (n=81), oral cavity (n=44), larynx (n=15), hypopharynx (n=10) and nasopharynx (n=6). The HPV status was examined in a randomly selected representative subcohort (n=38) using polymerase chain reaction. Of the 156 HNSCC samples, 81 (51.9%) and 54 (34.6%) were positive for IMP3 and p16, respectively. IMP3 expression (P=0.022), p16 expression (P<0.001) and the combination of these markers (P<0.001) were significantly associated with tumor site. In particular, 69/81 (85%) OPSCC samples were positive for either one or both markers compared with 36/75 (48%) SCC samples from other sites. p16 expression was significantly associated with HPV infection (P=0.017) and a trend towards a negative association between IMP3 expression and HPV infection was observed (P=0.053). The results of the present study suggested that IMP3 and p16 are more frequently expressed in OPSCC compared with other HNSCCs. The prognostic impact of IMP3 on OPSCC remains to be investigated in a larger series with an extended follow-up period.
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OBJECTIVE: The development of breast cancer cells is linked to hypoxia. The hypoxia-induced factor HIF-1α influences metastasis through neovascularization. Hypoxia seems to decrease the responsiveness to hormonal treatment due to loss of estrogen receptors (ERs). Obesity is discussed to increase hypoxia in adipocytes, which promotes a favorable environment for tumor cells in mammary fat tissue, whereas, tumor cells profit from good oxygen supply and are influenced by its deprivation as target regions within tumors show. This review gives an overview of the current state on research of hypoxia and breast cancer in human adipose tissue. METHODS: A systematic literature search was conducted on PubMed (2000-2016) by applying hypoxia and/or adipocytes and breast cancer as keywords. Review articles were excluded as well as languages other than English or German. There was no restriction regarding the study design or type of breast cancer. A total of 35 papers were found. Eight studies were excluded due to missing at least two of the three keywords. One paper was removed due to Russian language, and one was dismissed due to lack of adherence. Seven papers were identified as reviews. After applying exclusion criteria, 18 articles were eligible for inclusion. RESULTS: Two articles describe the impairment of mammary epithelial cell polarization through hypoxic preconditioning. A high amount of adipocytes enhances cancer progression due to the increased expression of HIF-1α which causes the loss of ER α protein as stated in four articles. Four articles analyzed that increased activation of HIF's induces a series of transcriptions resulting in tumor angiogenesis. HIF inhibition, especially when combined with cytotoxic chemotherapy, holds strong potential for tumor suppression as stated in further four articles. In two articles there is evidence of a strong connection between hypoxia, oxidative stress and a poor prognosis for breast cancer via HIF regulated pathways. Acute hypoxia seems to normalize the microenvironment in breast cancer tissue and has proven to affect tumor growth positively as covered in two articles. CONCLUSION: This review indicates that the development of breast cancer is influenced by hypoxia. A high amount of adipocytes enhances cancer progression due to the increased expression of HIF-1α.
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Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.
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Ligamiento Genético , Predisposición Genética a la Enfermedad , Genoma Humano , Neoplasias de la Próstata/genética , Anciano , Salud de la Familia , Alemania , Humanos , Masculino , Persona de Mediana Edad , Linaje , Estadísticas no ParamétricasRESUMEN
BACKGROUND: To obtain prevalence estimates for key symptoms and features that can indicate the presence of obstructive sleep apnea (OSA) in a broad range of primary care settings. DESIGN: Cross-sectional survey. SETTING: Forty offices and clinics in the United States, Germany, and Spain. PARTICIPANTS: Consecutive patients who were > 15 years of age, regardless of the reason for the visit. MEASUREMENTS: We collected demographic information, prevalence of self-reported chronic snoring, sleepiness, obesity (body mass index [BMI] > 30), hypertension, and calculation of OSA risk, and we also compared results between the United States and Europe. RESULTS: There was a 78% return rate for 8,000 surveys (mean age, 51 years; age range, 15 to 98 years; 52% women). One third of participants (32%) had a high pretest probability for OSA, with a higher rate in the United States (35.8% of 3,915 participants) than in Europe (26.3% of 2,308 participants; p < 0.001; age-matched and sex-adjusted odds ratio [OR], 1.37; 95% confidence interval [CI], 1.16 to 1.61). Sleepiness (32.4% vs 11.8%, respectively; p < 0.001) followed by obesity and/or hypertension (44.8% vs 37.1%, respectively; p < 0.01) contributed to the OSA risk difference between participants in the United States and Europe, as frequent snoring and breathing pauses were similarly reported (44%). A high pretest probability for OSA was more often present in men than in women (37.9% vs 27.8%, respectively; p < 0.005; OR, 1.96; CI, 1.59 to 2.88) and in those that were obese (ie, BMI, > or = 30 kg/m(2)), a condition that is generally more common in the US population than in the European population (27.9% vs 17.2%, respectively; p < 0.01). CONCLUSIONS: Primary care physicians in the United States and Europe will encounter a high demand for services to confirm or manage sleep apnea, sleepiness, and obesity.
Asunto(s)
Síndromes de la Apnea del Sueño/diagnóstico , Encuestas y Cuestionarios , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Atención Primaria de Salud , Factores de Riesgo , Síndromes de la Apnea del Sueño/epidemiología , Estados UnidosRESUMEN
AIM: Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa. METHODS: IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly. CONCLUSION: High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma/química , Mucosa Gástrica/química , Gastritis/metabolismo , Inmunohistoquímica , Proteínas de Unión al ARN/análisis , Neoplasias Gástricas/química , Proteína p53 Supresora de Tumor/análisis , Biopsia , Carcinoma/patología , Proliferación Celular , Diagnóstico Diferencial , Mucosa Gástrica/patología , Gastritis/patología , Humanos , Clasificación del Tumor , Valor Predictivo de las Pruebas , Neoplasias Gástricas/patologíaRESUMEN
Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that mildly predict prostate cancer risk. These SNPs are local tagging markers for causal gene alterations. Consideration of candidate genes in the tagged regions would be facilitated by additional information on the particular pathomechanisms which contribute to the observed risk increase. In this study we test for an association of prostate cancer tagging SNPs with alterations in DNA repair capacity, a phenotype that is frequently involved in cancer predisposition. DNA repair capacity was assessed on blood lymphocytes from 128 healthy probands after ionizing irradiation. We used the micronucleus (MN) assay to determine the cellular DNA double-strand break repair capacity and flow cytometry to measure damage induced mitotic delay (MD). Probands were genotyped for a panel of 14 SNPs, each representing an independent prostate cancer risk locus previously identified by GWAS. Associations between germline variants and DNA repair capacity were found for the SNPs rs1512268 (8p21), rs6983267 (8q24) and rs10993994 (10q11). The most significant finding was an association of homozygous rs10993994 T-allele carriers with a lower MN frequency (p=0.0003) and also a decreased MD index (p=0.0353). Cells with prostate cancer risk alleles at rs10993994 seem to cope more efficiently with DNA double strand breaks (less MN) in a shorter time (decreased MD index). This intriguing finding imposes concern about the accuracy of repair, with respect to the cancer risk that is mediated by T genotypes. To date, MSMB (microseminoprotein ß) is favored as the causal gene at the 10q11 risk locus, since it was the first candidate gene known to be expressionally altered by rs10993994. Based on the present observation, candidate genes from the contexts of DNA repair and apoptosis may be more promising targets for expression studies with respect to the rs10993994 genotype.