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BACKGROUND: We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance two years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. METHODS: Women with stage I-III HR+/HER2- breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance (EORTC QLQ-C30≥40/100) two years after diagnosis (year-2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, IL-1 receptor antagonist, TNF-α, and C-reactive protein), and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. RESULTS: Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year-2. High pre-treatment levels of IL-6 (Quartile 4 vs.1) were associated with global CRF at year-2 (adjusted Odds Ratio [aOR]: 2.06 [95% Confidence Interval 1.40-3.03]; p=0.0002; AUC=0.74). Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese (62.4%; mean BMI 28.0 [SD 6.3] Kg/m2) and physically inactive (53.5% did not meet WHO recommendations). Clinical and behavioral associations with CRF at year-2 included pre-treatment CRF (aOR vs no: 3.99 [2.81-5.66]), younger age (per 1-year decrement: 1.02 [1.01-1.03]), current smoking (vs never: 1.81 [1.26-2.58]), and worse insomnia or pain (per 10-unit increment: 1.08 [1.04-1.13], and 1.12 [1.04-1.21], respectively). Secondary analyses indicated additional associations of IL-2 (aOR per log-unit increment:1.32 [CI 1.03-1.70]) and IL-10 (0.73 [0.57-0.93]) with global CRF and of C-reactive protein (1.42 [1.13-1.78]) with cognitive CRF at year-2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. CONCLUSIONS: This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance two years later among a large prospective sample of survivors of breast cancer.
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BACKGROUND: Sexual concerns are a major unaddressed need among survivors of breast cancer (BC) with significant negative effects on quality of life. We longitudinally analyzed sexual health over time, using patient-reported outcomes. METHODS: Patients with stage I-III BC prospectively included from the CANcer TOxicity cohort (CANTO) provided data at diagnosis, then 1, 2, and 4 years afterward. Sexual concerns outcomes included poor body image (score ≤91/100), poor sexual functioning (≤16/100), poor sexual enjoyment (≤66/100), and sexual inactivity (EORTC QLQ-B23). Multivariate generalized estimating equation models assessed associations with sexual concerns after diagnosis, adjusting for age, sociodemographic, tumor, treatment, and clinical characteristics. RESULTS: Nearly 78.1% among 7895 patients reported at least one sexual concern between diagnosis and 4 years' follow-up. Over time, the proportion of patients reporting sexual concerns either increased or remained constant with diagnosis. Less than half (46%, range 11.4-57) of the patients with sexual concerns reported the use of supportive care strategies, including gynecological or psychological consultations (range 11.4-57.4). Factors consistently associated with sexual concerns up to 4 years after diagnosis included already reporting the same concern at diagnosis [odds ratio (OR)poor body image 3.48 [95% confidence interval (CI) 3.11-3.89]; ORsexual inactivity 9.94 (95% CI 8.84-11.18), ORpoor sexual function 9.75 (95% CI 8.67-10.95), ORpoorsexual enjoyment 3.96 (95% CI 3.34-4.69)], endocrine therapy use [ORpoor body image 1.15 (95% CI 1.01-1.31); ORsexual inactivity 1.19 (95% CI 1.02-1.39), ORpoor sexual function 1.17 (95% CI 1.01-1.37), ORpoor sexual enjoyment 1.23 (95% CI 1.00-1.53)], and depression [ORpoor body image 2.00 (95% CI 1.72-2.34); ORsexual inactivity 1.66 (95% CI 1.40-1.97), ORpoor sexual function 1.69 (95% CI 1.43-2.00), ORpoor sexual enjoyment 1.94 (95% CI 1.50-2.51)]. Outcome-specific associations were also identified. CONCLUSIONS: Sexual concerns seem frequent, persistent, and insufficiently addressed. Pretreatment concerns, endocrine therapy, and emotional distress are commonly associated factors. A proactive evaluation of sexual health across the care continuum is needed, to promptly identify patients suitable for multidisciplinary counseling, referral, and supportive interventions.
Assuntos
Neoplasias da Mama , Saúde Sexual , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/psicologia , Qualidade de Vida , Sobreviventes/psicologia , Medidas de Resultados Relatados pelo PacienteRESUMO
Gene discoveries in cancer have the potential for clinical and public health applications. To take advantage of such discoveries, a translational research agenda is needed to take discoveries from the bench to population health impact. To assess the current status of translational research in cancer genetics, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Year 2007, as well as the cancer genetic research articles published in 2007. We classified both funded grants and publications as follows: T0 as discovery research; T1 as research to develop a candidate health application (e.g., test or therapy); T2 as research that evaluates a candidate application and develops evidence-based recommendations; T3 as research that assesses how to integrate an evidence-based recommendation into cancer care and prevention; and T4 as research that assesses health outcomes and population impact. We found that 1.8% of the grant portfolio and 0.6% of the published literature was T2 research or beyond. In addition to discovery research in cancer genetics, a translational research infrastructure is urgently needed to methodically evaluate and translate gene discoveries for cancer care and prevention.
Assuntos
Neoplasias/genética , Pesquisa Translacional Biomédica , Medicina Baseada em Evidências , Pesquisa em Genética , Humanos , Literatura de Revisão como AssuntoRESUMO
BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.
Assuntos
Genes p16 , Heterozigoto , Melanoma/genética , Mutação , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/genética , Adulto , Austrália , Inibidor p16 de Quinase Dependente de Ciclina/genética , Europa (Continente) , Feminino , Cor de Cabelo , Humanos , Masculino , Nevo/complicações , Nevo/genética , América do Norte , Fenótipo , Medição de Risco , Fatores de Risco , Pigmentação da Pele , Queimadura Solar/complicações , População Branca/genéticaRESUMO
Novel methods that could improve the power of conventional methods of gene discovery for complex diseases should be investigated. In a simulation study, we aimed to investigate the value of molecular haplotypes in the context of a family-based linkage study. The term "haplotype" (or "haploid genotype") refers to syntenic alleles inherited on a single chromosome, and we use the term "molecular haplotype" to refer to haplotypes that have been determined directly by use of a molecular technique such as long-range allele-specific polymerase chain reaction. In our study, we simulated genotype and phenotype data and then compared the powers of analyzing these data under the assumptions that various levels of information from molecular haplotypes were available. (This information was available because of the simulation procedure.) Several conclusions can be drawn. First, as expected, when genetic homogeneity is expected or when marker data are complete, it is not efficient to generate molecular haplotyping information. However, with levels of heterogeneity and missing data patterns typical of complex diseases, we observed a 23%-77% relative increase in the power to detect linkage in the presence of heterogeneity with heterogeneity LOD scores >3.0 when all individuals are molecularly haplotyped (compared with the power when only standard genotypes are used). Furthermore, our simulations indicate that most of the increase in power can be achieved by molecularly haplotyping a single individual in each family, thereby making molecular haplotyping a valuable strategy for increasing the power of gene mapping studies of complex diseases. Maximization of power, given an existing family set, can be particularly important for late-onset, often-fatal diseases such as cancer, for which informative families are difficult to collect.
Assuntos
Simulação por Computador , Ligação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Haplótipos/genética , Genótipo , Humanos , Linhagem , SoftwareRESUMO
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
Assuntos
Adenoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hiperparatireoidismo/genética , Neoplasias das Paratireoides/genética , Proteínas/genética , Adenoma/patologia , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1 , Éxons , Etiquetas de Sequências Expressas , Genes Supressores de Tumor , Ligação Genética , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Fases de Leitura Aberta , Neoplasias das Paratireoides/química , Neoplasias das Paratireoides/patologia , Linhagem , Proteínas/química , Síndrome , Proteínas Supressoras de TumorRESUMO
OBJECTIVE: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families. METHODS AND RESULTS: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. CONCLUSIONS: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.
Assuntos
Colágeno Tipo VI/genética , Doenças Musculares/genética , Mutação/genética , Linhagem , Adolescente , Adulto , Idoso , Criança , Cromossomos Humanos Par 21/genética , Feminino , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , FenótipoRESUMO
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
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Endorribonucleases/genética , Mutação em Linhagem Germinativa , Oncogenes , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Nucleotídeos de Adenina/metabolismo , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Ligação Genética , Heterozigoto , Homozigoto , Humanos , Perda de Heterozigosidade , Linfócitos/enzimologia , Masculino , Oligorribonucleotídeos/metabolismo , LinhagemRESUMO
The study of complex genetic traits in humans is limited by the expense and difficulty of ascertaining populations of sufficient sample size to detect subtle genetic contributions to disease. Here we introduce an application of a somatic cell hybrid construction strategy called conversion that maximizes the genotypic information from each sampled individual. The approach permits direct observation of individual haplotypes, thereby eliminating the need for collecting and genotyping DNA from family members for haplotype-based analyses. We describe experimental data that validate the use of conversion as a whole-genome haplotyping tool and evaluate the theoretical efficiency of using conversion-derived haplotypes instead of conventional genotypes in the context of haplotype-frequency estimation. We show that, particularly when phenotyping is expensive, conversion-based haplotyping can be more efficient and cost-effective than standard genotyping.
Assuntos
Haplótipos/genética , Células Híbridas/fisiologia , Desequilíbrio de Ligação/genética , Animais , Cromossomos Humanos/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Células Híbridas/citologia , Hibridização in Situ Fluorescente , Masculino , Camundongos , Reação em Cadeia da PolimeraseRESUMO
Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.
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Oncogenes , Neoplasias da Próstata/genética , Alelos , Cromossomos Humanos Par 1/genética , Ligação Genética , Marcadores Genéticos , Humanos , Islândia , Escore Lod , Masculino , Cromossomo X/genéticaRESUMO
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
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Neoplasias da Mama/genética , Efeito Fundador , Genes BRCA1/genética , Mutação/genética , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Proteína BRCA2 , Neoplasias da Mama/patologia , Família , Feminino , Finlândia/epidemiologia , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Fatores de Tempo , Fatores de Transcrição/metabolismoRESUMO
The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.
Assuntos
Perfilação da Expressão Gênica , Melanoma/classificação , Neoplasias Cutâneas/classificação , Adulto , Análise por Conglomerados , Progressão da Doença , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/genética , Células Tumorais Cultivadas , Neoplasias Uveais/classificação , Neoplasias Uveais/genéticaRESUMO
A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
Assuntos
Neoplasias da Mama/genética , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Predisposição Genética para Doença/genética , Idoso , Proteína BRCA2 , Neoplasias da Mama/patologia , Mapeamento Cromossômico , Progressão da Doença , Feminino , Genes BRCA1/genética , Genoma Humano , Genótipo , Mutação em Linhagem Germinativa/genética , Haplótipos/genética , Humanos , Células Híbridas , Escore Lod , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Linhagem , Fatores de Transcrição/genéticaRESUMO
Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPC1 at 1q24-q25 (OMIM #601518) and HPCX at Xq27-q28 (OMIM #300147). Genetically homogeneous populations, such as that of Finland, and distinct subsets of families may help to minimize the genetic heterogeneity that complicates the genetic dissection of complex traits. Here, the role of the HPC1, and HPCX loci in a series of Finnish prostate cancer families was studied, especially in subgroups of families defined by age, number of affected cases, and the mode of disease transmission. DNA samples were collected from 57 Finnish HPC families with at least two living prostate cancer patients. Linkage analysis was carried out with 39 microsatellite markers for the HPC1 region and 22 markers for the HPCX region. The maximum two-point LOD score for the HPCX was 2.05 (marker DXS1205, at theta = 0.14), whereas HPC1 LOD scores were all negative. In HOMOG3R analyses, significant evidence of heterogeneity was observed. Subgroup analyses performed to explore the nature of this heterogeneity indicated that families with no male-to-male (NMM) transmission and a late age of diagnosis (>65 years) accounted for most of the HPCX-linked cases. The maximum HPCX LOD score in this subgroup was 3.12 (theta = 0.001). Nonparametric sibling pair analyses gave a peak LOD score of 3.04 (P < 0.000093) for the NMM transmission subgroup. No subgroup showed any positivity for HPC1. This study suggests that the HPCX-linked prostate cancer families represent a distinct subgroup characterized by NMM transmission of disease and late age of diagnosis.
Assuntos
Ligação Genética , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Idade de Início , Cromossomos Humanos Par 1 , Saúde da Família , Feminino , Finlândia , Predisposição Genética para Doença , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Cromossomo XRESUMO
Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Síndrome da Retração Ocular/genética , Substituição de Aminoácidos , Códon/genética , Análise Mutacional de DNA , Síndrome da Retração Ocular/fisiopatologia , Feminino , Genes Dominantes/genética , Genes Homeobox/genética , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , México , Repetições de Microssatélites/genética , Mutação/genética , Linhagem , PenetrânciaRESUMO
Cataracts are a significant public health problem. Here, we describe the genetic alteration responsible for a progressive form of cataract, segregating as an autosomal dominant trait in a three-generation pedigree. Unlike most autosomal dominant cataracts, these are not clinically apparent at birth but are initially observed in the first year or two of life. The opacification evolves relatively slowly, generally necessitating removal of the lens in childhood or early adolescence. A genome-wide search in our kindred revealed linkage at 2q33-35 where the gamma-crystallin gene cluster resides. A single base alteration resulting in an Arg- 14 --> Cys (R14C) substitution in gammaD-crystallin was subsequently identified. Protein modeling suggests that the effect of this mutation is a subtle one, affecting the surface properties of the crystallin molecule rather than its tertiary structure, consistent with the fact that the patients' lenses are normal at birth. This is the first gene defect shown to be responsible for a noncongenital progressive cataract, and studying the defective protein should teach us more about the mechanisms underlying cataract formation.
Assuntos
Catarata/genética , Cristalinas/química , Cristalinas/genética , Mutação Puntual , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Estrutura Secundária de Proteína , Idade de Início , Animais , Catarata/fisiopatologia , Bovinos , Éxons , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Núcleo Familiar , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
Several genetic epidemiological studies have provided data to support the hypothesis that there are genes on the X chromosome that may contribute to prostate cancer susceptibility. A recent linkage study of 360 prostate cancer families described evidence for a prostate cancer predisposition gene, termed HPCX, which maps to Xq27-28. To confirm the potential contribution of this locus to prostate cancer susceptibility in an independent dataset, we studied 153 unrelated families who are participants in the University of Michigan Prostate Cancer Genetics Project. Families selected for this analysis have at least two living family members with prostate cancer that are related in a way that they could potentially share a common ancestral copy of an X chromosome. DNA samples were genotyped using a panel of seven polymorphic markers spanning 30 cM and containing the HPCX candidate region. The resulting data were analyzed using both nonparametric and parametric linkage methods. Analysis of all 153 families using multipoint non-parametric linkage (NPL) methods resulted in positive NPL Z-scores across the entire candidate interval (NPL Z-scores of 0.23-1.06, with corresponding one-sided Ps of 0.41 and 0.15, respectively). The 11 African-American families had negative NPL Z-scores across the same 30-cM interval. Analysis of the 140 Caucasian families produced a maximal NPL Z-score of 1.20, with a corresponding one-sided P of 0.12 at marker DXS1113. The subset of families with no evidence of male-to-male disease transmission and with early-onset prostate cancer (average age at diagnosis within a family < or = 65 years) contributed disproportionately to the evidence for linkage for the entire dataset in the HPCX candidate region (near marker DXS1113). In conclusion, this study of 153 families, each with two or more living members with prostate cancer, provides some additional support for the existence of a prostate cancer susceptibility gene at Xq27-28.
Assuntos
Ligação Genética , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Cromossomo X , Idoso , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Linhagem , Fatores Sexuais , Estatísticas não ParamétricasRESUMO
Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Cromossomo X , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Marcadores Genéticos , Genótipo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Receptores Androgênicos/genéticaRESUMO
Plasma gamma-hexachlorocyclohexane (gamma-HCH) and three urinary trichlorophenols were measured in forestry workers who were engaged in planting seedlings treated with gamma-HCH. These two procedures were assessed as potential biological monitoring methods and the data were compared with reported clinical symptoms. The measurement of plasma gamma-HCH was considered to be a feasible and valid monitoring method for use in routine practice and is a useful indicator of gamma-HCH absorption. The data were used to illustrate the need to be vigilant about personal hygiene and the efficacy of protective clothing. Plasma gamma-HCH concentrations above 70 nmol/l were measured in two workers which coincided with persistent non-specific clinical symptoms. Trichlorophenols were identified in urine but the extensive and variable metabolism of gamma-HCH makes this approach less suitable for biological monitoring.