RESUMEN
OBJECTIVE: Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice. METHOD: Tumours and blood samples from 262 successive patients with colorectal adenocarcinomas were collected. Expression of the MMR proteins MLH1, MSH2, and MSH6 by immunohistochemistry (IHC) was compared with MSI DNA analysis. Methylation analysis of MLH1 and mutation analysis for BRAF V600E were compared in samples with MSI and/or lack of MLH1 expression to determine if the tumour was likely to be sporadic. RESULTS: Thirty-nine (14.9%) of the tumours showed MMR deficiency by IHC or by microsatellite analysis. Sporadic inactivation by methylation of MLH1 promoter was found in 35 patients whereby the BRAF activating V600E mutation, indicating sporadic origin, was found in 32 tumours. On the basis of molecular characteristics we found 223 patients with intact MMR, 35 patients with sporadic MMR deficiency, and four patients who were likely to have hereditary MMR deficiency. CONCLUSION: To obtain the maximal benefit for patients and clinicians, MMR testing should be supplemented with MLH1 methylation or BRAF mutation analysis to distinguish sporadic patients from likely hereditary ones. MMR deficient patients with sporadic disease can be reassured of the better prognosis and the likely hereditary cases should receive genetic counselling.
Asunto(s)
Adenocarcinoma/clasificación , Adenocarcinoma/genética , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Adulto , Anciano , Anciano de 80 o más Años , Metilación de ADN , Proteínas de Unión al ADN/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/análisis , Proteína 3 Homóloga de MutS , MutaciónRESUMEN
A total of 392 men referred for intracytoplasmic sperm injection (ICSI) participated in genetic analysis. The control group consisted of 100 normal fertile males. Chromosome and DNA analyses were performed to investigate the frequency of Y-chromosome microdeletions and CFTR mutations (the controls underwent DNA analysis only). An abnormal karyotype was found in 4.6% of all males, but the frequency among men with azoospermia was higher, at 11.7%. Y-chromosome microdeletions were found only among men with azoospermia (6.5%) and men with extreme oligospermia (2%). Compound heterozygosity for CFTR mutations was found in men with azoospermia (3.9%) and congenital bilateral absence of vas deferens (CBAVD) only. We conclude that all couples referred for ICSI should be offered chromosome analysis. DNA analysis for Y-chromosome microdeletions should be reserved for men with azoospermia or extreme oligospermia (<1 x 106 spermatozoa). Analysis for CFTR mutations should be limited to those with obstructive azoospermia or those with a family history of cystic fibrosis.
Asunto(s)
Pruebas Genéticas , Inyecciones de Esperma Intracitoplasmáticas , Adulto , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Y/genética , Cromosomas Humanos Y/ultraestructura , Fibrosis Quística/epidemiología , Fibrosis Quística/genética , Fibrosis Quística/prevención & control , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Análisis Mutacional de ADN , Tamización de Portadores Genéticos , Humanos , Cariotipificación , Masculino , Mosaicismo , Oligospermia/genética , Aberraciones Cromosómicas Sexuales , Recuento de Espermatozoides , Conducto Deferente/anomalíasRESUMEN
Resistance to activated protein C (APC) is the most prevalent single phenomenon associated with thromboembolic disease. It is caused by a single point mutation in the factor V gene (Arg506Gln or FV Leiden), replacing an Arg506 with a Gln at the APC-cleavage site in factor V. In this study we present a prevalence study of the Arg506Gln mutation in a large Danish cohort. By screening 4188 newborns (8376 alleles) we identified 3.4% alleles (95% CI: 3.0-3.8) of the Arg506Gln mutation, corresponding to a heterozygous prevalence of 6.6% (95% CI: 5.9-7.4) in Denmark. This is significantly lower than what has been reported from southern Sweden. The birth cohort has been selected from the entire country, providing representative and accurate estimates of the gene frequencies. Equal gender distribution was found, and the Arg506Gln mutation is probably not a considerable risk factor in fetal life in the general population.