RESUMEN
Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Reparación de la Incompatibilidad de ADN/genética , Etiopía , Mutación de Línea Germinal , Humanos , Judíos/genética , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Adulto JovenRESUMEN
Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.
Asunto(s)
Neoplasias Colorrectales/genética , Exoma , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Adulto , Neoplasias Colorrectales/patología , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Humanos , Masculino , Metiltransferasas/genética , Persona de Mediana Edad , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 13/genética , Secuenciación del ExomaRESUMEN
Purpose. A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called missing heritability. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. Methods/patients. We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. Results. We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. Conclusions. These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC (AU)
No disponible
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Neoplasias Colorrectales/genética , Micronúcleo Germinal/genética , Mutación de Línea Germinal , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Colorrectales/complicaciones , Neoplasias/genética , Células Germinativas/patología , Predisposición Genética a la Enfermedad/etiología , Micronúcleo Germinal/patologíaRESUMEN
PURPOSE: A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS: We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS: These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Variaciones en el Número de Copia de ADN/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas del Tejido Nervioso/genética , Edad de Inicio , Metilación de ADN , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Pérdida de Heterocigocidad , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2.
Asunto(s)
Adenosina Trifosfatasas/genética , Secuencia de Bases , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Eliminación de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Exones , Femenino , Mutación del Sistema de Lectura , Pruebas Genéticas , Inestabilidad Genómica , Mutación de Línea Germinal , Humanos , Repeticiones de Microsatélite , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa Multiplex , Tasa de Mutación , EspañaRESUMEN
Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.
Asunto(s)
Cromosomas Humanos Par 11 , Neoplasias Colorrectales/genética , Dosificación de Gen , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos , Ensayos Clínicos Fase II como Asunto , Neoplasias Colorrectales/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Farmacogenética , Polimorfismo de Nucleótido Simple/genética , Resultado del TratamientoAsunto(s)
Secuencia de Bases , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Cromosomas Humanos Par 10 , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Eliminación de Secuencia , Edad de Inicio , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.
Asunto(s)
Cromosomas Humanos Par 3 , Cromosomas Humanos Par 9 , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Anciano , Antígenos CD/genética , Proteínas Portadoras/genética , Estudios de Casos y Controles , Proteínas de Unión al ADN/genética , Proteínas Ligadas a GPI/genética , Estudios de Asociación Genética , Humanos , Masculino , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Semaforinas/genéticaRESUMEN
Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. The novel MSH2 c.[2635-3T>C; 2635-5C>T] mutation was identified in 4 Lynch families, cosegregating with the disease. This mutation, located in intron 15, was predicted to alter the correct mRNA processing by in silico analysis. Our aim was to perform the c.[2635-3T>C; 2635-5C>T] mutation screening in high risk CRC cases and control populations, to evaluate the founder effect in our population by haplotype analysis and to confirm the pathogenic effect of the mutation by MSH2 expression studies. Mutation screening was performed by SSCP and CSCE in genomic DNA from 323 high risk CRC cases and 289 controls. Haplotyping was performed analysing 4 MSH2 extragenic microsatellite markers (D2S288, D2S2227, D2S1247 and D2S1248) in 50 controls and mutation carriers by using the PHASE program. We analysed the effect of the mutation in mRNA processing by RT-PCR and in MSH2 expression by qRT-PCR using RNA from 5 mutation carriers and 18 controls. None of the remaining high risk CRC cases or controls analysed harboured the mutation. We identified a common telomeric haplotype and two centromeric haplotypes, both rare in our population. Although we were not able to identify any abnormal transcript by RT-PCR with the design used, we observed a significant reduction of mRNA MSH2 expression in carriers when compared with controls. Haplotype analyses suggest a founder effect of the c.[2635-3T>C; 2635-5C>T] MSH2 mutation and expression studies support a pathogenic role of this mutation.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Efecto Fundador , Proteína 2 Homóloga a MutS/genética , Empalme Alternativo/genética , Exones/genética , Familia , Femenino , Haplotipos/genética , Humanos , Masculino , Linaje , EspañaRESUMEN
It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.
Asunto(s)
Neoplasias Colorrectales/genética , Polimorfismo Genético , Predisposición Genética a la Enfermedad , Humanos , Penetrancia , Pronóstico , Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: Several models have recently been developed to predict mismatch repair (MMR) gene mutations. Their comparative performance with clinical criteria or universal molecular screening in a population based colorectal cancer (CRC) cohort has not been assessed. METHODS: All 1222 CRC from the EPICOLON cohort underwent tumour MMR testing with immunohistochemistry and microsatellite instability, and those with MMR deficiency (n = 91) underwent MLH1/MSH2 germline testing. Sensitivity, specificity and positive predictive value (PPV) of the PREMM(1,2) and the Barnetson models for identification of MLH1/MSH2 mutation carriers were evaluated and compared with the revised Bethesda guidelines (RBG), Amsterdam II criteria, and tumour analysis for MMR deficiency. Overall discriminative ability was quantified by the area under the ROC curve (AUC), and calibration was assessed by comparing the average predictions versus the observed prevalence. RESULTS: Both models had similar AUC (0.93 and 0.92, respectively). Sensitivity of the RBG and a PREMM(1,2) score > or =5% was 100% (95% CI 71% to 100%); a Barnetson score >0.5% missed one mutation carrier (sensitivity 87%, 95% CI 51% to 99%). PPVs of all three strategies were 2-3%. Presence of MMR deficiency increased specificity and PPV of predictive scores (97% and 21% for PREMM(1,2) score > or =5%, and 98% and 21% for Barnetson > or =0.5%, respectively). CONCLUSIONS: The PREMM(1,2) and the Barnetson models offer a quantitative systematic approach to select CRC patients for identification of MLH1/MSH2 mutation carriers with a similar performance to the RBG.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Análisis Mutacional de ADN , Tamización de Portadores Genéticos/métodos , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Homólogo 1 de la Proteína MutLRESUMEN
The knowledge acquired in genetics and molecular biology over the last 2 decades has led to advances in the molecular diagnosis of some diseases, among them hereditary forms of colorectal cancer such as hereditary non-polyposis colorectal cancer and familial adenomatous polyposis. Moreover, the discovery of the genes causing these diseases has had implications beyond hereditary diseases since the same genes that cause hereditary forms of cancer also play a role in the much more frequent sporadic forms. Genetic diagnosis allows clinical diagnosis to be confirmed, as well as presymptomatic and even prenatal diagnoses to be made, with implications for patients with these hereditary diseases and their families.
Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Genética Médica/métodos , Síndromes Neoplásicos Hereditarios/genética , Adenocarcinoma/diagnóstico , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Algoritmos , Pólipos del Colon/diagnóstico , Pólipos del Colon/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN , Reparación del ADN/genética , Genes APC , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Hamartoma/diagnóstico , Hamartoma/genética , Humanos , Síndromes Neoplásicos Hereditarios/diagnósticoRESUMEN
Los conocimientos adquiridos en genética y biología moleculares a lo largo de las 2 últimas décadas han permitido progresar en el diagnóstico molecular de algunas enfermedades, entre ellas las formas de cáncer colorrectal hereditario como el cáncer colorrectal hereditario no polipósico y la poliposis adenomatosa familiar. El descubrimiento de los genes causantes de estas enfermedades ha tenido, además, repercusiones más allá de las propias enfermedades hereditarias, ya que en muchas ocasiones los mismos genes causantes de las formas hereditarias de cáncer también participan en las formas esporádicas mucho más frecuentes. El diagnóstico genético permite la confirmación de un diagnóstico clínico, la realización de un diagnóstico presintomático o incluso prenatal, con las consecuencias que ello implica para los pacientes afectados de estas enfermedades hereditarias y sus familias
The knowledge acquired in genetics and molecular biology over the last 2 decades has led to advances in the molecular diagnosis of some diseases, among them hereditary forms of colorectal cancer such as hereditary non-polyposis colorectal cancer and familial adenomatous polyposis. Moreover, the discovery of the genes causing these diseases has had implications beyond hereditary diseases since the same genes that cause hereditary forms of cancer also play a role in the much more frequent sporadic forms. Genetic diagnosis allows clinical diagnosis to be confirmed, as well as presymptomatic and even prenatal diagnoses to be made, with implications for patients with these hereditary diseases and their families
Asunto(s)
Humanos , Adenocarcinoma/genética , Genética Médica/métodos , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Colorrectales/genética , Adenocarcinoma/diagnóstico , Algoritmos , Pólipos del Colon/diagnóstico , Pólipos del Colon/genética , Análisis Mutacional de ADN , Reparación del ADN/genética , Genes APC , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Hamartoma/diagnóstico , Hamartoma/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genéticaRESUMEN
AIM: To establish the usefulness of KRAS mutational analysis in the diagnosis of pancreatic adenocarcinoma by comparing this technique with conventional cytology in aspirates obtained by endosonography-guided fine-needle aspiration. METHODS: All consecutive patients with pancreatic focal lesions undergoing endosonography-guided fine-needle aspiration were included. Samples were obtained with the concurrence of an attendant cytopathologist. Detection of codon-12 KRAS mutations was performed by the restriction fragment length polymorphism-polymerase chain reaction method. The effectiveness of conventional cytology, KRAS mutational analysis and their combination was established with respect to the definitive diagnosis. A cost-effectiveness analysis was also performed. RESULTS: Thirty-three patients had pancreatic adenocarcinoma and 24 patients had other lesions. A total of 136 samples was obtained. In patients in whom specimens were adequate (93% for cytology; 100% for mutational analysis), the specificity of both techniques was 100%, whereas the sensitivity favoured cytology (97% vs. 73%). When inadequate samples were considered as misdiagnosed, a combination of both techniques reached the highest overall accuracy (cytology, 91%; mutational analysis, 84%; combination of both, 98%). CONCLUSIONS: Cytology from aspirates obtained by endosonography-guided fine-needle aspiration is the most precise single technique for the diagnosis of pancreatic adenocarcinoma. However, when adequate specimens are not available to reach a cytological diagnosis, the addition of KRAS mutational analysis represents the best strategy.
Asunto(s)
Adenocarcinoma/diagnóstico , Análisis Mutacional de ADN/normas , Neoplasias Pancreáticas/diagnóstico , Biopsia con Aguja/métodos , Análisis Costo-Beneficio , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Estudios Prospectivos , Sensibilidad y Especificidad , Ultrasonografía IntervencionalRESUMEN
INTRODUCTION: Because of the increased complexity of the diagnostic-therapeutic approach to colorectal cancer (CRC), these patients should be managed in specialized multidisciplinary units. The aim of this study was to evaluate the efficacy and efficiency of a CRC unit (CRCU) in the diagnostic-therapeutic management of these patients. PATIENTS AND METHODS: Two groups of 50 patients with colon cancer treated in our center before and after the implementation of the CRCU were selected. Fulfillment with the protocol in terms of tumoral staging, surgical and adjuvant treatment, follow-up, interval until treatment, hospital stay, morbidity and early mortality, and the overall duration of the diagnostic-therapeutic process was analyzed. In addition, clinical workload was evaluated and a cost-minimization analysis was performed. RESULTS: The CRCU reduced the interval until surgery (20.3 12.0 vs 28.0 20.4 days; p = 0.05), hospital stay (9.8 7.7 vs 14.5 9.3 days: p = 0.01), the time to the start of adjuvant treatment (29.4 10.2 vs 39.7 19.8 days; p = 0.03) and the overall duration of the process (60.4 23,8 vs 82.1 46.1 days; p = 0.05), representing a saving of 978.85 E per patient. This improvement took place despite an increase in clinical workload (24% in 5 years in relation to the number of admissions) and had no effect on morbidity (26 vs 24%; NS) or immediate mortality (6 vs 4%; NS). CONCLUSION: Specialized multidisciplinary units increase the efficacy and efficiency of the management of patients with CRC.
Asunto(s)
Neoplasias Colorrectales/terapia , Prestación Integrada de Atención de Salud , Evaluación de Programas y Proyectos de Salud , Anciano , Neoplasias Colorrectales/economía , Eficiencia Organizacional , Femenino , Costos de Hospital , Unidades Hospitalarias/economía , Humanos , Relaciones Interprofesionales , Tiempo de Internación/economía , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the relationship between the FMR1 premutation and premature ovarian failure (POF) in the Spanish population and the possible incorporation of this test in gynecological procedures for women with POF or early menopause (EM). DESIGN: Clinical and molecular genetic study. Ninety-eight premutated and six full-mutated carriers of fragile X syndrome and 43 women with POF were studied by polymerase chain reaction and Southern blot analysis for the CGG repeat expansion in the FMR1 gene. RESULTS: Among premutated carriers, 12.2% (12 of 98) presented with POF, and 15.3% (15 of 98) presented with EM. Neither POF nor EM was observed in any of the six full-mutated women. Two women of 43 from the POF population (4.65%) were carriers for the CGG premutation in the FMR1 gene. No correlation between CGG expansion size and age at menopause was found. A biased paternal origin of the premutation and a high twinning incidence was found in all premutated women, whether they had POF or not. CONCLUSIONS: Our data support the hypothesis that the FMR1 gene is one of the genes associated with POF and EM. Analysis of the CGG expansion in the FMR1 gene may be justified in women with POF and EM until the real role of the FMR1 premutation is determined.
Asunto(s)
Menopausia Prematura/genética , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN , Adulto , Envejecimiento , Southern Blotting , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/genética , Humanos , Linaje , Reacción en Cadena de la Polimerasa , Insuficiencia Ovárica Primaria/genética , España , GemelosRESUMEN
Mental retardation (MR) is a genetically heterogeneous, clinically variable condition. Many cases of MR are linked to the X chromosome. The aim of this study was to identify candidate loci for nonspecific MR in Spanish samples. We selected seven families with nonspecific MR and a pattern of inheritance compatible with an X-linked disorder and a group of 26 sib pairs of mentally retarded individuals. We performed linkage analysis with a panel of 15 markers evenly distributed along the X chromosome. The study showed linkage to marker DXS8076, located in Xq21.1, by the lod score method (z = 2.11 at straight theta = 0.155) and the nonparametric extended relative pair analysis method (chi(2) = 5.32; P < 0.03). Genetic heterogeneity was found, with an estimated 75% of the families linked at recombination fraction straight theta = 0.10 to the DXS8076 locus (chi(2) = 9.51; P < 0.009). Xq13-q21 is one of the critical regions for X-linked MR previously reported, and our study supports the idea that this region may contain a locus for MR in Spanish patients.
Asunto(s)
Discapacidad Intelectual/genética , Cromosoma X/genética , ADN/genética , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Programas Informáticos , EspañaRESUMEN
Mental retardation (MR) is a group of heterogeneous clinical conditions. There are more than 900 genetic disorders associated with MR and it affects around 3% of the general population. MR can be subdivided into syndromic, if it is characterized by consistent and distinctive clinical findings, and nonspecific, if mental retardation is the only primary symptom among affected individuals. Many MR conditions described are syndromic, fragile X syndrome being the most common clinical entity among them. In the past years, knowledge of the molecular basis of mental retardation has increased remarkably. Eight genes involved in nonspecific X-linked MR have been identified so far, including FMR2, OPHN1, GDI1, PAK3, IL1RAPL, TM4SF2, VCX-A, and ARHGEF6. Two other genes also located on the X chromosome have been involved both in syndromic and in MRX forms (RSK2 and XNP/ATR-X). New insights into the pathogenesis of mental retardation are being provided by the discovery of these genes involved in different cellular signaling pathways in the central nervous system although many others remain to be identified.
Asunto(s)
Discapacidad Intelectual/genética , Clonación Molecular , Exones , Femenino , Síndrome del Cromosoma X Frágil/genética , Humanos , Masculino , Modelos Genéticos , Cromosoma XRESUMEN
Molecular screening programs in mentally retarded individuals have been performed in several populations worldwide. One finding has been an excess of FMR1 intermediate alleles in a population with learning difficulties. However, other published reports with similar characteristics did not corroborate those previous results. In order to contribute additional data from our population, we studied 563 patients affected with nonspecific mental retardation (MRX) that did not present a CGG expansion in the FMR1 gene and 208 individuals as a control population. Forty MRX patients presented alleles within the intermediate range. Among them, one case showed a pattern of expression of the FMR1 protein (FMRP) concordant with a fragile X syndrome case with an intermediate allele/full mutation mosaicism, although it was not detected by Southern blot analysis. Statistical analysis was performed again showing no statistically significant difference regarding the intermediate allele frequency in the MRX and control populations. This finding is in agreement with the hypothesis that the incidence of intermediate FMR1 alleles in MRX populations does not seem to be higher than in control populations, and it emphasizes the importance of FMRP detection as a diagnostic tool for fragile X syndrome.