RESUMO
BACKGROUND: Polypectomy may be performed at colonoscopy and then subsequent surveillance undertaken. It is thought that faecal haemoglobin concentration (f-Hb), estimated by quantitative faecal immunochemical tests (FIT), might be a useful tumour marker. METHODS: Consecutive patients enrolled in colonoscopy surveillance were approached at two hospitals. A specimen for FIT was provided before colonoscopy and, ideally after 3 weeks, a second FIT sample from those who had polypectomy. A single FIT system (OC-Sensor io, Eiken Chemical Co., Ltd) was used to generate f-Hb. RESULTS: 1103 Patients were invited; 643 returned a FIT device (uptake: 58.3%). Four patients had known inflammatory bowel disease (IBD) and were excluded, leaving 639 (57.9%) with an age range of 25-90 years (median 64 years), 54.6% male. Of 593 patients who had a f-Hb result and completed colonoscopy, advanced neoplasia was found in 41 (6.9%); four colorectal cancer (CRC): 0.7% and 37 advanced adenoma (AA): 6.3%, and a further 127 (21.4%) had non-advanced adenoma (NAA). The median f-Hb was significantly greater in AA as compared to NAA; 6.0 versus 1.0 µg Hb/g faeces, p < 0.0001.134/164 (81.7%) of invited patients returned a second FIT device: 28 were patients with AA in whom median pre-polypectomy f-Hb was 19.2, falling to 3.5 µg Hb/g faeces post-polypectomy, p = 0.01, and 106 with NAA had median pre-polypectomy f-Hb 0.8 compared to 1.0 µg Hb/g faeces post-polypectomy, p = 0.96. CONCLUSIONS: Quantitative FIT could provide a good tumour marker in post-polypectomy surveillance, reduce colonoscopy requirements and minimise potential risk to patients.
Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Detecção Precoce de Câncer , Fezes/química , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Sangue OcultoRESUMO
BACKGROUND: Quantitative faecal immunochemical tests measure faecal haemoglobin concentration (f-Hb), which increases in the presence of colorectal neoplasia. OBJECTIVE: We examined the diagnostic accuracy of faecal immunochemical test (FIT)in patients at increased risk of colorectal cancer (CRC) attending for surveillance colonoscopy as per national guidelines. METHODS: A total of 1103 consecutive patients were prospectively invited to complete a FIT before their scheduled colonoscopy in two university hospitals in 2014- 2016. F-Hb was analysed on an OC-Sensor io automated analyser (Eiken Chemical Co., Ltd, Tokyo, Japan) with a limit of detection of 2 µg Hb/g faeces. The diagnostic accuracy of f-Hb for CRC and higher-risk adenoma was examined. RESULTS: A total of 643 patients returned a faecal test. After excluding 4 patients with known inflammatory bowel disease, 639 (57.9%) remained in the study: age range: 25-90 years (median: 64 years, interquartile range (IQR): 55-71): 54.6% male. Of 593 patients who also completed colonoscopy, 41 (6.9%) had advanced neoplasia (4 CRC, 37 higher-risk adenoma). Of the 238 patients (40.1%) who had detectable f-Hb, 31 (13.0%) had advanced neoplasia (2 CRC, 29 higher-risk adenoma) compared with 10 (2.8%) in those with undetectable f-Hb (2 CRC, 8 higher-risk adenoma). Detectable f-Hb gave negative predictive values of 99.4% for CRC and 97.2% for CRC plus higher-risk adenoma. CONCLUSION: In patients at increased risk of CRC under colonoscopy surveillance, a test measuring faecal haemoglobin can provide an objective estimate of the risk of advanced neoplasia, and could enable tailored scheduling of colonoscopy.
Assuntos
Adenoma/epidemiologia , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Hemoglobinas/análise , Adenoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sangue Oculto , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricosRESUMO
Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.
RESUMO
Multiple self-healing squamous epithelioma (MSSE) is a rare familial skin cancer in which multiple tumours resembling crateriform squamous carcinomas are locally invasive but regress spontaneously after several months, leaving deep disfiguring facial scars and shallower scars on the limbs. First identified in a number of Scottish families, the condition has since been reported more widely. We review here the investigations leading to the discovery of loss of function mutations in TGFBR1 that are responsible for the disease. Loss of heterozygosity in tumours reveals that TGFBR1 acts as a tumour suppressor gene. TGFBR1 was initially excluded as the MSSE gene because it lies outside an extensive chromosome 9 haplotype shared by Scottish families. MSSE can now be regarded as a digenic/multilocus disease in view of the evidence of a second linked locus necessary for pathogenesis located within the Scottish haplotype. This article is part of a Directed Issue entitled: Rare Cancers.
Assuntos
Carcinoma/genética , Ceratoacantoma/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias Cutâneas/genética , Carcinoma/etiologia , Carcinoma/patologia , Cromossomos Humanos Par 9 , Cicatriz/genética , Cicatriz/patologia , Haplótipos , Humanos , Ceratoacantoma/etiologia , Ceratoacantoma/patologia , Perda de Heterozigosidade/genética , Mutação , Receptor do Fator de Crescimento Transformador beta Tipo I , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologiaAssuntos
Carcinoma/genética , Cromossomos Humanos Par 9/genética , Variação Genética/genética , Ceratoacantoma/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Dermatopatias/genética , Carcinoma/etnologia , Estudos de Casos e Controles , Mutação em Linhagem Germinativa/genética , Humanos , Ceratoacantoma/etnologia , Receptores Patched , Polimorfismo de Nucleotídeo Único/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Superfície Celular/genética , Escócia , Dermatopatias/etnologiaRESUMO
BACKGROUND: Lifestyle influences breast cancer risk. Women at increased familial risk may benefit from modifying behaviour, but it is not known to what extent they do so. PURPOSE: This study aims to measure changes that UK (Scottish) women make in response to increased familial risk of breast cancer and attitudes to a risk-reduction trial. METHODS: A questionnaire, completed by 140 "breast cancer family" clinic patients, generated data on habitual diet, alcohol consumption and exercise, changes made after learning of breast cancer risk and attitudes to possible further changes. Subgroups of patients were defined by criteria likely to influence changes in behaviour. Between-group differences were analysed by Fisher's exact test and overall correlations by linear regression. RESULTS: Thirty-six subjects (26 %) reported no behavioural change but, overall, around 25 % of diet, exercise and alcohol items had been changed. Women perceiving their lifetime cancer risk to be high (>50 %) and those who were obese (BMI >25) had made significantly more changes than others. Younger women (<40 years) and those with daughters had made fewer changes. Almost all suggested elements of a risk-reduction trial were strongly supported. CONCLUSIONS: Scottish women at increased risk of breast cancer have scope for protective changes in lifestyle and support a risk-reduction trial. The needs of younger women and of those with daughters should be addressed in its design.
Assuntos
Atitude Frente a Saúde , Neoplasias da Mama/prevenção & controle , Controle Interno-Externo , Estilo de Vida , Comportamento de Redução do Risco , Adulto , Consumo de Bebidas Alcoólicas/prevenção & controle , Neoplasias da Mama/genética , Exercício Físico , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/prevenção & controle , Análise de Regressão , Fatores de Risco , Escócia , Prevenção do Hábito de Fumar , Inquéritos e Questionários , MulheresRESUMO
Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin-binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular , Proteínas de Transporte/genética , Haploinsuficiência , Poroceratose/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Mapeamento Cromossômico , Citosol/ultraestrutura , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Linhagem , Poroceratose/metabolismo , Ligação Proteica , Proteínas/genética , Proteínas/metabolismoRESUMO
Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.
Assuntos
Mutação , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias Cutâneas/genética , Sequência de Aminoácidos , Sequência de Bases , Carcinoma/genética , Carcinoma/metabolismo , Códon sem Sentido , Sequência Conservada , Primers do DNA/genética , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Haplótipos , Humanos , Ceratoacantoma/genética , Ceratoacantoma/metabolismo , Masculino , Síndrome de Marfan/genética , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/química , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Homologia de Sequência de Aminoácidos , Neoplasias Cutâneas/metabolismoRESUMO
ATRX belongs to the SNF2 family of proteins, many of which have been demonstrated to have chromatin remodeling activity. Constitution mutations in the X-encoded gene give rise to alpha thalassemia mental retardation (ATR-X) syndrome and a variety of related conditions that are often associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Acquired mutations in ATRX are observed in the preleukemic condition alpha thalassemia myelodysplastic syndrome (ATMDS). Mutations in ATRX have been shown to perturb gene expression and DNA methylation. This is a comprehensive report of 127 mutations including 32 reported here for the first time. Missense mutations are shown to cluster in the two main functional domains. The truncating mutations appear to be "rescued" to some degree and so it appears likely that most if not all constitutional ATRX mutations are hypomorphs.
Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Proteínas Nucleares/genética , Talassemia alfa/genética , Sequência de Bases , Códon sem Sentido , DNA Helicases/química , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Proteínas Nucleares/química , Estrutura Terciária de Proteína , Proteína Nuclear Ligada ao XRESUMO
Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith Disease, is a rare cancer-associated genodermatosis with an autosomal dominant inheritance. Affected patients suffer from recurrent skin lesions, which clinically and histologically resemble keratoacanthomas or well-differentiated squamous cell carcinomas, but which, if left, undergo spontaneous regression, leaving pronounced scarring. The majority of MSSE cases previously described were of Scottish ancestry and all shared the same at-risk haplotype, suggesting that this disorder was caused by a founder mutation. The candidate locus for MSSE lies in a region of <4 cM in chromosome 9q22, between the markers D9S197 and D9S1809. We recently investigated MSSE families of non-Scottish origin. For every patient of these families, we obtained a detailed clinical history, with particular attention to the age of onset, distribution, and clinical course of their skin lesions. Once confirmed that they were really affected by MSSE, we performed haplotype analysis on them and their families. The haplotypes for polymorphic markers segregating with MSSE in non-Scottish and Scottish families differ, suggesting that MSSE is not caused by a founder mutation and might be more common than originally thought.
Assuntos
Carcinoma/etnologia , Carcinoma/genética , Efeito Fundador , Mutação/genética , Neoplasias Cutâneas/etnologia , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Criança , Feminino , Predisposição Genética para Doença , Testes Genéticos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Remissão Espontânea , Escócia , Neoplasias Cutâneas/patologiaRESUMO
Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.
Assuntos
Dermatite Atópica/genética , Ictiose Vulgar/genética , Proteínas de Filamentos Intermediários/genética , Mutação Puntual , Dermatite Atópica/epidemiologia , Saúde da Família , Feminino , Proteínas Filagrinas , Ligação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Ictiose Vulgar/epidemiologia , Irlanda/epidemiologia , Masculino , Linhagem , Fenótipo , PrevalênciaRESUMO
Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder. Two nonsense mutations, eight single missense mutations, three allelic double missense mutations, and two are polymorphisms were identified in the biotinidase gene (BTD). One of the missense mutations, c.734G>A (p. C245Y), is the first to be reported that alters the cysteine in the putative location crucial for ester formation and binding of the biotinyl-moiety in the active site of the enzyme. These mutations add to the growing list of mutations that are helping to delineate structure/function relationships of the enzyme.