RESUMEN
BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies.
Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Factores de Transcripción Forkhead/genética , Interferón gamma/genética , Factor de Necrosis Tumoral alfa/genética , Adenocarcinoma/patología , Secuencia de Bases , Neoplasias Colorrectales/patología , Cartilla de ADN , Femenino , Expresión Génica , Humanos , Masculino , Inestabilidad de Microsatélites , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de SupervivenciaRESUMEN
BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , ARN/genética , Telomerasa/genética , Telómero/química , Adenoma/genética , Anciano , Carcinoma/genética , Estudios de Casos y Controles , Femenino , Técnicas de Genotipaje , Células HCT116 , Humanos , Leucocitos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Telómero/genéticaRESUMEN
AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.
Asunto(s)
Pólipos del Colon/genética , Neoplasias Colorrectales/genética , Síndrome de Hamartoma Múltiple/genética , Fosfohidrolasa PTEN/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Pólipos del Colon/etiología , Neoplasias Colorrectales/etiología , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/complicaciones , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Persona de Mediana EdadRESUMEN
Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.
Asunto(s)
Síndrome de Peutz-Jeghers/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Niño , Preescolar , Endoscopía Gastrointestinal , Medicina Basada en la Evidencia/métodos , Femenino , Neoplasias Gastrointestinales/diagnóstico , Neoplasias de los Genitales Femeninos/diagnóstico , Genotipo , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Fenotipo , Vigilancia de la Población/métodos , Adulto JovenRESUMEN
It is widely accepted that tumors are monoclonal in origin, arising from a mutation or series of mutations in a single cell and its descendants. The clonal origin of colonic adenomas and uninvolved intestinal mucosa from an XO/XY mosaic individual with familial adenomatous polyposis (FAP) was examined directly by in situ hybridization with Y chromosome probes. In this patient, the crypts of the small and large intestine were clonal, but at least 76 percent of the microadenomas were polyclonal in origin.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Colon/patología , Mucosa Intestinal/patología , Mosaicismo , Poliposis Adenomatosa del Colon/patología , Adulto , Células Clonales , Sondas de ADN , Genotipo , Humanos , Íleon/patología , Hibridación in Situ , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Fenotipo , Cromosoma YRESUMEN
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.
Asunto(s)
Exones , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Eliminación de Secuencia , Quinasas de la Proteína-Quinasa Activada por el AMP , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Masculino , Mutación , Técnicas de Amplificación de Ácido Nucleico , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/epidemiología , Mutación PuntualRESUMEN
OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Adulto , Alelos , Análisis por Conglomerados , Análisis Mutacional de ADN , Genes ras , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Persona de Mediana Edad , Modelos Genéticos , MutaciónRESUMEN
Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.
Asunto(s)
Cromosomas Humanos Par 10/genética , Neoplasias Gastrointestinales/genética , Genes Supresores de Tumor/genética , Síndrome de Hamartoma Múltiple/genética , Pólipos/genética , Mutación de Línea Germinal , Haplotipos , Humanos , Escala de Lod , Repeticiones de Microsatélite , Síndrome de Peutz-Jeghers/genéticaRESUMEN
PURPOSE: Hereditary nonpolyposis colon cancer (HNPCC) is a Mendelian dominant syndrome of bowel, endometrial, and other cancers and results from germline mutations in mismatch repair (MMR) genes. HNPCC is now best diagnosed on molecular grounds using MMR mutation screening, aided by microsatellite instability (MSI) and immunohistochemistry in tumors. Selection of families for molecular investigation of HNPCC is usually based on suboptimal methods (Amsterdam Criteria or Bethesda Guidelines), but these can be improved using additional clinical data (mean ages of affected persons and presence of endometrial cancer) in a quantitative model. METHODS: We have verified the performance of the Wijnen model and have shown that it remains valid when HNPCC is diagnosed using mutation screening, MSI, and immunohistochemistry. We have also set up and verified our own models (Amsterdam-plus and Alternative), which perform at least as well as the Wijnen model. RESULTS: The Amsterdam-plus model improves on the Amsterdam Criteria by using five extra variables (numbers of colorectal and endometrial cancers in the family, number of patients with five or more adenomas, number with more than one primary cancer of the colorectum or endometrium, and mean age of presentation) and performs better than the Wijnen model. The Alternative model avoids the need to evaluate the Amsterdam Criteria and performs nearly as well as the other models. CONCLUSION: We believe that a quantitative model, such as the Amsterdam-plus model, should be the first choice for selecting families or patients for evaluation of HNPCC using molecular tests. We present an algorithm for this process.
Asunto(s)
Algoritmos , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Reparación del ADN/genética , Neoplasias Endometriales/genética , Predisposición Genética a la Enfermedad , Modelos Teóricos , Guías de Práctica Clínica como Asunto , Adulto , Disparidad de Par Base , Femenino , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Factores de RiesgoRESUMEN
Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.
Asunto(s)
Proteínas de Unión al ADN , Anemia de Fanconi/genética , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica/fisiología , Leucemia Mieloide/genética , Proteínas/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Metilación de ADN , Regulación hacia Abajo , Exones , Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación A de la Anemia de Fanconi , Femenino , Silenciador del Gen , Humanos , Leucemia Mieloide/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Regiones Promotoras Genéticas , Proteínas/metabolismo , Eliminación de SecuenciaRESUMEN
Fanconi anaemia (FA) is an autosomal recessive disease characterised by congenital abnormalities, defective haemopoiesis, and a high risk of developing acute myeloid leukaemia and certain solid tumours. Chromosomal instability, especially on exposure to alkylating agents, may be shown in affected subjects and is the basis for a diagnostic test. FA can be caused by mutations in at least seven different genes. Interaction pathways have been established, both between the FA proteins and other proteins involved in DNA damage repair, such as ATM, BRCA1 and BRCA2, thereby providing a link with other disorders in which defective DNA damage repair is a feature. This review summarises the clinical features of FA and the natural history of the disease, discusses diagnosis and management, and puts the recent molecular advances into the context of the cellular and clinical FA phenotype.
Asunto(s)
Anemia de Fanconi , Animales , Aberraciones Cromosómicas , Reparación del ADN/genética , Diagnóstico Diferencial , Progresión de la Enfermedad , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiología , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética , HumanosRESUMEN
Mutations in the RP2 gene located on Xp11.23 are associated with X-linked retinitis pigmentosa (XLRP), a severe form of progressive retinal degeneration which leads to complete loss of vision in affected males. To date, 14 different mutations in the RP2 gene have been reported to cause XLRP, the majority of which lead to a coding frameshift within the gene and predicted truncation of the protein product. We here report two novel frameshift mutations in RP2 identified in XLRP families by PCR-SSCP and direct sequencing, namely 723delT and 796-799del. Four single nucleotide polymorphisms (SNPs) within the coding region of RP2 are also described (105A>T, 597T>C, 844C>T, 1012G>T), the first polymorphisms to be reported within this gene of unknown function, two of which alter the amino acid sequence. The current study extends the XLRP mutation profile of RP2 and highlights non-pathogenic coding sequence variations which may facilitate both functional studies of the gene and analysis of intragenic allelic contribution to the phenotype.
Asunto(s)
Proteínas del Ojo , Mutación del Sistema de Lectura/genética , Variación Genética/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/genética , Empalme Alternativo/genética , Proteínas de Unión al GTP , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de la Membrana , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Mutations in the Ataxia Telangiectasia Mutated (ATM) gene are responsible for the autosomal recessive disease Ataxia Telangiectasia (A-T). A wide variety of mutations scattered across the entire coding region (9168bp) of ATM have been found, which presents a challenge in developing an efficient mutation screening strategy for detecting unknown mutations. Fluorescent chemical cleavage of mismatch (FCCM) is an ideal mutation screening method, offering a non-radioactive alternative to other techniques such as restriction endonuclease fingerprinting (REF). Using FCCM, we have developed an efficient, accurate and sensitive mutation detection method for screening RT-PCR products for ATM mutations. We have identified seven ATM mutations in five A-T families, four of which are previously unknown. We quantified ATM protein expression in four of the families and found variable ATM protein expression (0-6.4%), further evidence for mutant ATM protein expression in both classic and variant A-T patients. We conclude that FCCM offers a robust ATM mutation detection method and can be used to screen for ATM mutations in cancer-prone populations.
Asunto(s)
Ataxia Telangiectasia/genética , Colorantes Fluorescentes , Mutación , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Adolescente , Adulto , Alelos , Empalme Alternativo , Proteínas de la Ataxia Telangiectasia Mutada , Western Blotting , Proteínas de Ciclo Celular , Niño , Preescolar , Proteínas de Unión al ADN , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Mutación Missense , Juego de Reactivos para Diagnóstico , Factores de Tiempo , Proteínas Supresoras de TumorRESUMEN
We report the results of screening for molecular deletions in 164 boys with DMD and BMD and correlation of deletions with clinical features. A deletion was detected in 100 cases (61%) by Southern blot hybridization analysis with cDNA probes. Thirty-eight different deletions and two duplications were identified. All deletions except one (deletion of exons 48-53) found in males with DMD disrupted the translational reading frame of the gene; however, six deletions in boys with BMD were out of frame. The same deletion in different individuals was found to occur with or without mental impairment, and many different deletions were associated with mental retardation. We were able to ascertain a series of boys [from this study and a previous one (Hodgson S V, Hart K, Abbs S, et al. Correlation of clinical and deletion data in Duchenne and Becker muscular dystrophy. J Med Genet 1989; 26: 682-693)] without significant mental retardation who had deletions which, when combined, covered the whole region of the gene in which deletions are commonly found, and within which region individual deletions can be associated with mental retardation.
Asunto(s)
Distrofina/genética , Discapacidad Intelectual/genética , Distrofias Musculares/complicaciones , Distrofias Musculares/genética , Adolescente , Adulto , Niño , Preescolar , ADN/análisis , Sondas de ADN , Exones/genética , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Eliminación de SecuenciaRESUMEN
Further DNA linkage studies on two previously described X-linked recessive Emery-Dreifuss muscular dystrophy (EMD) families are reported, which refine the localization of the gene responsible for EMD. Two recombination events indicate that the most likely localization for the EMD gene lies in the interval between DXS15/DXS52 and F8C. A maximum LOD score of 3.44 at theta = 0 is obtained for EMD vs the red and green cone pigment genes (RCP and GCP). Our data provide additional support for one of the two proposed orientations of genes and markers distal to DXS15/DXS52, with respect to the telomere. Given this favoured orientation, our data best fit a localization of EMD to within a 2 megabase (Mb) interval between DXS15/DXS52 and F8C.
Asunto(s)
Color del Ojo/genética , Factor VIII/genética , Distrofias Musculares/genética , Células Fotorreceptoras/metabolismo , Adolescente , Southern Blotting , Genes Recesivos , Ligamiento Genético , Humanos , Masculino , Distrofia Muscular de Emery-Dreifuss , Hibridación de Ácido Nucleico , Linaje , Cromosoma XRESUMEN
The Oculo-cerebro-renal syndrome of Lowe is an X-linked recessive disorder characterised by mental and growth retardation, renal rickets with renal tubular acidosis, generalised aminoaciduria, hypotonia, cataracts, glaucoma and frontal bossing. Manifestations of this syndrome were seen in a girl with no family history of the disorder, but who was found to have a de novo balanced X/3 translocation, with a breakpoint at Xq25. She had also inherited a balanced 14/17 translocation from her father. It is postulated that the clinical picture may be the result of disruption of the X chromosome within the gene at the locus for Lowe syndrome, with non-random inactivation of the normal X, which may permit the expression of this X-linked recessive disorder in a girl.
Asunto(s)
Cromosomas Humanos 1-3 , Síndrome Oculocerebrorrenal/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Translocación Genética , Cromosoma X , Niño , Mapeo Cromosómico , Cromosomas Humanos 13-15 , Cromosomas Humanos 16-18 , Femenino , Genes Recesivos , Ligamiento Genético , Humanos , Cariotipificación , Linfocitos/ultraestructura , MutaciónRESUMEN
It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Adulto , Quinasa de Punto de Control 2 , Femenino , Frecuencia de los Genes , Genes APC , Humanos , Masculino , Mutación , Linaje , Fenotipo , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
The expression of the tumour suppressor gene p53 was analyzed in a variety of human solid tumours by immunohistochemistry and direct DNA sequencing. Positive nuclear staining using a panel of anti-p53 antibodies was used to select tumours for further genetic analysis. Using PCR amplification followed by immobilization onto magnetic beads and direct sequencing, we sequenced exons 5-9 of the p53 gene from 9 melanomas, 8 nasopharyngeal carcinomas, 16 sporadic breast carcinomas and 11 patients from familial breast cancer families. No sequence alterations of the p53 gene were detected in either the melanoma or nasopharyngeal tumours and only 19% of the primary breast carcinomas showed a variant band indicative of a mutation. Our results indicate firstly that p53 mutations are not generally involved in the tumour types studied and secondly the data emphasize the disparity encountered when attempting to correlate p53 immunohistochemical positivity with mutations within the p53 gene.
Asunto(s)
Inmunohistoquímica , Mutación , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Mama/genética , ADN/química , Análisis Mutacional de ADN , Femenino , Genes p53 , Humanos , Melanoma/genética , Neoplasias Nasofaríngeas/genética , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Inherited cancer syndromes may predispose to more than one type of cancer, and these characteristically develop at an earlier age than their sporadic counterparts. The occurrence in a single individual of multiple, early onset primary cancers may indicate an inherited cancer susceptibility. Familial adenomatous polyposis (FAP), an autosomal, dominantly inherited susceptibility to colorectal adenomas and cancer also predisposes to childhood medulloblastomas and to a specific rare histologic type (cribriform variant) of papillary thyroid cancer. We describe a patient who developed a childhood medulloblastoma of the cerebellum, and subsequently a cribriform papillary thyroid cancer. These cancers predated the diagnosis of FAP in this patient, who was later found to have several relatives with FAP. The adenomatous polyposis coli (APC) mutation delineated in this family was in the region associated with those causing an increased risk of thyroid cancer. We submit that the diagnosis of the cribriform variant of papillary thyroid cancer in a young individual, especially after a previous cancer diagnosis, should alert the physician to the possibility of a diagnosis of FAP.
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Adenocarcinoma Papilar/genética , Poliposis Adenomatosa del Colon/genética , Variación Genética , Neoplasias de la Tiroides/genética , Neoplasias Cerebelosas/genética , Resultado Fatal , Femenino , Humanos , Meduloblastoma/genética , Persona de Mediana Edad , Mutación , LinajeRESUMEN
We present our experience so far of screening individuals referred to the Cancer family clinic at St. Mark's Hospital from 1986, with the results of the follow-up of these individuals. 651 individuals from 436 families were offered colonoscopic surveillance at five-yearly intervals. The median age at which the examination was performed was 41 years. Families were subdivided according to family history; 15.8% conformed to the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC). The pathological findings were correlated with the type of pedigree; abnormalities were more often found in males than females (30% of colonoscopies in males revealed adenomas, and 17% in females), and adenoma prevalence increased with age. Adenoma prevalence (27% v.s. 21% at all ages, and 38% v.s. 25% in individuals over the age of 35y.), multiple adenomas and the proportion of proximally sited adenomas were all higher in HNPCC families; however, dysplasia and villous or large adenomas were not more common in individuals from HNPCC families. Four of the 7 carcinoma detected were in HNPCC families (3% v.s. 0.6%).