RESUMEN
BACKGROUND: Growing evidence suggests that some individuals may exhibit symptoms of dependence on ultraviolet (UV) light, a known carcinogen, in the context of tanning; however, few studies have investigated predictors of tanning dependence (TD). OBJECTIVE: To identify predictors of TD. METHODS: Non-Hispanics of European ancestry who had previously participated in a case-control study of early-onset basal cell carcinoma completed an online survey to ascertain TD and other behaviours (alcohol dependence, nicotine dependence, seasonal affective disorder (SAD), exercise 'addiction' and depression). Information on host factors, such as skin and eye colour and history of sunbathing and indoor tanning, was obtained from a study in which the participants were previously enrolled. Lifetime TD was assessed using the modified Cut down, Annoyed, Guilty, Eye-opener (mCAGE) and the modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (mDSM-IV-TR) questionnaires. Participants were classified as 'TD' if positive on both questionnaires and not TD if negative on both questionnaires. RESULTS: In total, 499 individuals completed the online survey (81.9% participation rate), and 24.4% were classified as 'TD'. In the multivariate model, women were more likely to be TD [odds ratio (OR) 6.93; 95% confidence intervals (95% CI) (3.36-14.27)] than men. Alcohol dependence (OR 6.55: 95% CI 3.19-13.42), SAD (OR 2.77; 95% CI 1.26-6.09) and exercise 'addiction' (OR 5.47; 95% CI 1.15-26.06) were all significant predictors for TD. CONCLUSION: Increased knowledge of those at risk for TD will allow appropriate interventions to be designed.
Asunto(s)
Conducta Adictiva , Baño de Sol , Población Blanca , Adulto , Estudios de Casos y Controles , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Previous epidemiological studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) radiation, this has not been evaluated in existing epidemiological studies. OBJECTIVES: To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. METHODS: Basal cell carcinoma cases (n = 380) and controls with benign skin conditions (n = 390) under 40 years of age were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage, during an in-person interview. Self-reported data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CIs) using unconditional multivariate logistic regression in the full sample and in women only. RESULTS: There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall [above median intake vs. no regular alcohol intake (OR 1·10, 95% CI 0·69-1·73)] or in women only (OR 1·21, 95% CI 0·73-2·01). Similarly, intake of red wine, white wine, beer or spirits and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (P(interaction) = 0·003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping CIs. CONCLUSIONS: Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC.
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Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma Basocelular/etiología , Neoplasias Cutáneas/etiología , Adulto , Edad de Inicio , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Baño de Sol/estadística & datos numéricos , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversosRESUMEN
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
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Carcinoma Endometrioide/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Receptores de Progesterona/genética , Adulto , Anciano , Carcinoma Endometrioide/patología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Mutagénesis Insercional , Invasividad Neoplásica , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/patología , Factores de RiesgoRESUMEN
BACKGROUND: Linear unilateral basal cell nevus represents a linear collection of macules and papules histologically similar to basal cell carcinoma but with benign clinical behavior. We describe a patient who initially presented at the age of 6 months with a unilateral linear basal cell nevus on the right flank. The differential diagnosis included the nevoid basal cell carcinoma syndrome. Constitutional PTCH mutations are causative of the nevoid basal cell carcinoma syndrome, and somatic PTCH mutations are found in the vast majority of basal cell carcinomas. Somatic SMO mutations have also been found in some basal cell carcinomas. METHODS: Histologic examination of the lesions is performed. Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed. RESULTS: Histologic examination revealed features initially indistinguishable from basal cell carcinoma. Short tandem-repeat DNA analysis did not reveal loss of heterozygosity at the PTCH locus. DNA sequencing of both the PTCH and the SMO genes from the patient's lesions revealed neither inactivating mutations of PTCH nor activating mutations of SMO. CONCLUSION: Molecular examination indicates that the PTCH and SMO genes are not involved in the pathogenesis of the patients' congenital linear unilateral basal cell nevus. Furthermore, we discuss the relationship between linear basal cell nevus and basaloid follicular hamartoma.
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Nevo/genética , Nevo/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Muslo , ADN de Neoplasias , Diagnóstico Diferencial , Humanos , Lactante , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Mutación , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias Cutáneas/congénito , Receptor SmoothenedRESUMEN
The human patched gene (PTCH) functions in both embryologic development and tumor suppression. PTCH mutations have been found in odontogenic keratocysts. However, the expression and localization of the protein product of the gene have not been determined in odontogenic tumors and cysts. We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas. All odontogenic lesions, including two keratocysts with truncating mutations, were positive for PTCH. Different types of lesions had different amounts of staining. Lack of staining was noted in the majority of basal cell carcinomas. Taken together, these data suggest that odontogenic keratocysts arise with heterozygous mutations of the PTCH gene.
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Proteínas de la Membrana/análisis , Proteínas de Neoplasias/análisis , Quistes Odontogénicos/genética , Tumores Odontogénicos/genética , Secuencia de Aminoácidos , Carcinoma Basocelular/química , Carcinoma Basocelular/genética , Genes Supresores de Tumor , Heterocigoto , Humanos , Técnicas para Inmunoenzimas , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Mutación , Proteínas de Neoplasias/genética , Quistes Odontogénicos/química , Tumores Odontogénicos/química , Receptores Patched , Receptor Patched-1 , Receptores de Superficie CelularRESUMEN
Developmental pathways first elucidated by genetic studies in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with various human congenital anomalies. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations in some of these genes can result in cancer. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Although most BCCs are sporadic, in rare cases, individuals have a hereditary disease, Gorlin syndrome, that predisposes to multiple skin tumors as well as a variety of birth defects. Mutations in the human homolog of a Drosophila gene, patched, underlie Gorlin syndrome. Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumor formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for skin cancer and possibly other tumors.
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Carcinoma Basocelular/genética , Proteínas/genética , Neoplasias Cutáneas/genética , Transactivadores , Animales , Síndrome del Nevo Basocelular/genética , Carcinoma Basocelular/terapia , Drosophila , Predisposición Genética a la Enfermedad , Proteínas Hedgehog , Humanos , Proteínas de la Membrana/genética , Modelos Biológicos , Mutación , Receptores Patched , Receptores de Superficie Celular , Neoplasias Cutáneas/terapiaRESUMEN
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by the predisposition to develop both peptic ulcer disease and a wide variety of endocrine tumors usually in adolescence and adulthood. Specifically, hyperplasia and/or tumors (most often adenomas) of the parathyroid, pancreatic islet cells, anterior pituitary, and adrenal cortical glands are classically described in affected individuals who have MEN1 (1,2). MEN1 is a highly penetrant disorder whose onset is generally during adult life with the occurrence of at least one, but most often more than one, of the aforementioned tumors. The age-related penetrance of this disorder based on analysis in 63 unrelated kindreds is 7, 52, 87, 98, 99, and 100% by 10, 20, 30, 40, 50, and 60 yr, respectively (3). The disorder is estimated to occur in approx 1 in 30,000 to 1 in 50,000 individuals. Most cases are associated with a positive family history of the disorder, but new germline mutations have been identified in a small percentage of individuals having a negative family history of the disorder but classic features of MEN1 (3-7).
RESUMEN
OBJECTIVE: To note that a thyrotropin (TSH)-secreting macroadenoma may be part of the multiple endocrine neoplasia-1 (MEN-1) syndrome and to report the use of octreotide-LAR (OCT-LAR) to treat a TSH-secreting macroadenoma in a patient with MEN-1 with previous surgery for hyperparathyroidism and gastrinoma. METHODS: We present a patient with a TSH-secreting pituitary macroadenoma and report the results of her endocrine, genetic, radiologic, and nuclear medicine testing and her response to treatment with octreotide (OCT), octreotide-LAR, and estrogen. RESULTS: This patient's TSH-induced hyperthyroidism responded to octreotide for 5 months and octreotide-LAR for more than 11 months. Her hypercalcemia normalized while she was taking estrogen. Her genetic testing is reported to show a genetic defect that is typical of patients with MEN-1. CONCLUSION: This report describes: (1) The use of octreotide-LAR to treat both a TSH-secreting pituitary tumor and a gastrinoma over 12 months; (2) the importance of including these tumors into the MEN-1 syndrome with its attendant implications; and (3) a genetic defect, typical of patients with MEN-1, associated with this tumor.
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Adenoma/tratamiento farmacológico , Hormonas/administración & dosificación , Neoplasia Endocrina Múltiple Tipo 1/tratamiento farmacológico , Octreótido/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Tirotropina/metabolismo , Adenoma/diagnóstico por imagen , Adenoma/metabolismo , Estrógenos/administración & dosificación , Femenino , Humanos , Hipercalcemia/etiología , Hipertiroidismo/diagnóstico por imagen , Hipertiroidismo/tratamiento farmacológico , Hipertiroidismo/etiología , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico por imagen , Cintigrafía , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/metabolismoAsunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Basocelular/tratamiento farmacológico , Liliaceae/química , Proteínas de la Membrana/genética , Transactivadores , Alcaloides de Veratrum/farmacología , Animales , Síndrome del Nevo Basocelular/tratamiento farmacológico , Síndrome del Nevo Basocelular/genética , Síndrome del Nevo Basocelular/metabolismo , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Evaluación Preclínica de Medicamentos , Anomalías del Ojo/genética , Anomalías del Ojo/veterinaria , Proteínas Hedgehog , Humanos , Mutación , Receptores Patched , Proteínas/metabolismo , Receptores de Superficie Celular , Ovinos , Enfermedades de las Ovejas/genética , Transducción de Señal/efectos de los fármacosRESUMEN
An odontogenic keratocyst (OKC) is a benign cystic lesion of the jaws that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Recently, the gene for NBCCS was cloned and shown to be the human homologue of the Drosophila segment polarity gene Patched (PTCH), a tumor suppressor gene. The PTCH gene encodes a transmembrane protein that acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues, including tooth. We investigated three cases of sporadic odontogenic keratocysts and three other cases associated with NBCCS, looking for mutations of the PTCH gene. Non-radioactive single-strand conformational polymorphism and direct sequencing of PCR products revealed a deletion of 5 base pairs (bp) in exon 3 (518delAAGCG) in one sporadic cyst as well as mutations in two cysts associated with NBCCS, a nonsense (C2760A) and a missense (G3499A) alteration. This report is the first to describe a somatic mutation of PTCH in sporadic odontogenic keratocysts as well as two novel mutations in cysts associated with NBCCS, indicating a similar pathogenesis in a subset of sporadic keratocysts.
Asunto(s)
Proteínas de la Membrana/genética , Mutación/genética , Quistes Odontogénicos/genética , Transactivadores , Adulto , Sustitución de Aminoácidos/genética , Síndrome del Nevo Basocelular/genética , Emparejamiento Base/genética , Codón sin Sentido/genética , Inducción Embrionaria/genética , Exones/genética , Femenino , Mutación del Sistema de Lectura/genética , Eliminación de Gen , Genes Supresores de Tumor/genética , Proteínas Hedgehog , Humanos , Masculino , Mutación Missense/genética , Receptores Patched , Receptor Patched-1 , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas/genética , Receptores de Superficie Celular , Análisis de Secuencia de ADN , Transducción de Señal/genéticaRESUMEN
Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports.
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Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Proteínas de la Membrana/genética , Mutación/genética , Humanos , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular , Análisis de Secuencia de ADN/métodos , Células Tumorales CultivadasRESUMEN
Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.
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Carcinoma Medular/diagnóstico , Carcinoma Medular/genética , Mutación de Línea Germinal/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Carcinoma Medular/cirugía , Niño , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas/métodos , Genotipo , Humanos , Persona de Mediana Edad , Linaje , Fenotipo , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
OBJECTIVES AND STUDY DESIGN: Squamous cell carcinomas are common malignancies and a major cause of mortality. The molecular mechanisms involved in tumorigenesis remain largely unknown, but sequence alterations have been identified in coding regions of several genes. Primary squamous cell carcinomas of various tissues (skin, head and neck, esophagus, lung, penis, uterus, and vagina) from 52 patients were analyzed for the presence of mutations within several candidate genes presumably involved in tumorigenesis: Gsalpha, Gi2alpha, GTPase activating protein (GAP), and patched (PTCH) genes. METHODS: Mutational analysis scheme included polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE), single stranded conformational polymorphism (SSCP), and selected sequence analysis. RESULTS AND CONCLUSION: No tumor had any evidence of mutations in any of these analyzed genes. Mutations within these genes do not occur frequently in an unselected population of patients with squamous cell carcinomas.
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Carcinoma de Células Escamosas/genética , Mutación Puntual/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Exones/genética , Femenino , Proteínas de Unión al GTP/genética , Humanos , Masculino , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético/genéticaRESUMEN
Many genes originally identified because of their role in embryonic development are also important in postnatal control of cell growth and differentiation. Mutations in some of these genes have been shown to cause cancer. Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. More than 750000 new cases are diagnosed annually, and the incidence is rising. BCCs are slow-growing, locally invasive tumors that rarely metastasize but can result in extensive morbidity through local recurrence and tissue destruction. Epidemiologic studies suggest that sunlight (particularly UVB radiation) is a strong risk factor for BCC formation, although other factors are also involved. The nevoid basal cell carcinoma syndrome (NBCCS), a rare genetic disorder, is characterized by predisposition to BCCs and other tumors as well as to a wide range of developmental defects. NBCCS maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary BCCs suggests that it functions as a tumor suppressor. The gene for NBCCS was recently cloned and is the human homologue of the Drosophila gene "patched." Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, which is important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in both hereditary and sporadic BCCs, and inactivation of this gene is probably a necessary, if not sufficient, step for BCC formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for BCCs and possibly for other tumors associated with NBCCS.
Asunto(s)
Síndrome del Nevo Basocelular/genética , Carcinoma Basocelular/genética , Genes Supresores de Tumor/genética , Mutación , Neoplasias Cutáneas/genética , Animales , Síndrome del Nevo Basocelular/etiología , Carcinoma Basocelular/etiología , Clonación Molecular , Drosophila melanogaster/genética , Humanos , Fenotipo , Factores de Riesgo , Neoplasias Cutáneas/etiología , Rayos Ultravioleta/efectos adversosRESUMEN
PURPOSE: We report that patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome) are at risk for developing neoplasms, especially basal cell carcinomas and rarely medulloblastoma. METHODS: A case report is presented of a 5-year-old child with medulloblastoma and multiple basal cell carcinomas who was diagnosed with nevoid basal cell carcinoma syndrome. Genetic analyses were performed on tumor DNA from the patient's medulloblastoma and basal cell carcinoma as well as germline DNA from the patient and unaffected family members. RESULTS: After radiation therapy for medulloblastoma, the patient developed thousands of additional basal cell carcinomas. Analysis of tumor DNA revealed the characteristic defect of nevoid basal cell carcinoma syndrome, loss of heterozygosity at 9q22. Photodynamic therapy was successfully used to control the majority of her cutaneous tumors. CONCLUSION: DNA analysis confirmed the presence of the distinctive genetic lesion of nevoid basal cell carcinoma syndrome in both medulloblastoma and basal cell carcinoma. Omitting or limiting radiation therapy for children with nevoid basal cell carcinoma syndrome and medulloblastoma should be considered.
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Síndrome del Nevo Basocelular , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Primarias Múltiples , Neoplasias Cutáneas , Alelos , Síndrome del Nevo Basocelular/tratamiento farmacológico , Síndrome del Nevo Basocelular/genética , Biomarcadores de Tumor , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/radioterapia , Preescolar , ADN de Neoplasias/genética , Femenino , Humanos , Meduloblastoma/genética , Meduloblastoma/radioterapia , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/radioterapia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genéticaRESUMEN
Gorlin's syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a familial or hereditary predisposition to basal cell carcinomas (generally multiple and of early onset), odontogenic keratocysts (jaw cysts), palmar and plantar pits, a wide variety of developmental defects, as well as cancers such as medulloblastomas and ovarian fibromas. The gene for NBCCS has been mapped to human chromosome region 9q22.1-q31 by linkage analysis and by cytogenetic evidence of deletions in this region in patients with the syndrome. This is supported by loss of heterozygosity in tumors of polymorphic marker loci flanked by D9S197 and D9S180. We have utilized sequence tagged site (STS) mapping and somatic cell hybrid panel analysis to construct two overlapping yeast artificial chromosome (YAC) contigs spanning this region of the genome. We used the YAC contigs to identify a new zinc finger gene containing a highly informative microsatellite locus.