RESUMEN
BACKGROUND: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. METHODS: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. RESULTS: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above. CONCLUSION: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , Canadá/epidemiología , Neoplasias Colorrectales/epidemiología , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Persona de Mediana Edad , Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. OBJECTIVE: To investigate a panel of missense variants. METHODS AND RESULTS: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. CONCLUSIONS: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Mutación Missense , Neoplasias Ováricas/genética , Adolescente , Adulto , Algoritmos , Proteína BRCA1/química , Proteína BRCA1/clasificación , Proteína BRCA1/metabolismo , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Estructura Terciaria de Proteína , Activación TranscripcionalRESUMEN
The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.
Asunto(s)
Alelos , Neoplasias de la Mama/genética , Cromosomas Humanos Par 17 , Pérdida de Heterocigocidad , Adulto , Neoplasias de la Mama/patología , Femenino , Genes Supresores de Tumor , Marcadores Genéticos , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/genéticaRESUMEN
Most breast cancer has a complex, multifactorial etiology. One consequence of this multifactorial phenomenon is that etiological heterogeneity may exist. This heterogeneity implies simply that two or more groups of breast cancer cases in the general population may have been caused by different sets of events. The ability to define etiologically heterogeneous subgroups in the population may facilitate a number of research and clinical issues. Studying etiologically homogeneous subgroups in the general population may improve the ability to identify etiologic agents. Identification of a homogeneous group of breast cancer cases may also aid breast cancer diagnosis or treatment, and may allow a more effectively application of cancer prevention and control strategies. Defining etiologic heterogeneity in the general population is one initial step in the process of understanding cancer etiology. Using knowledge such as that provided in the two examples presented here, formal case-control or cohort studies can be undertaken to examine whether the factors that define etiologic heterogeneity are involved in etiology. Furthermore, the results of studies of etiologic heterogeneity can point toward potential gene-gene or gene-environment interactions. The type of studies presented here can therefore serve a useful role in leading to more formal molecular epidemiological analyses.
Asunto(s)
Neoplasias de la Mama/etiología , Carcinógenos Ambientales/efectos adversos , Marcadores Genéticos , Edad de Inicio , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Genética de Población , Humanos , Factores de RiesgoRESUMEN
The gene predisposing to neurofibromatosis type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals. These patients display a marked variability in clinical presentation, ranging from very severe disease with numerous tumors at a young age to a relatively mild condition much later in life. To investigate whether this phenotypic heterogeneity is determined by the type of mutation in NF2, we have collected clinical information on 111 NF2 cases from 73 different families on whom we have performed mutation screening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. These include 26 proposed protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), 6 splice-site mutations, 2 missense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in other NF2 individuals or sporadic tumors. When individuals harboring protein-truncating mutations are compared with cases with single codon alterations, a significant correlation (P < .001) with clinical outcome is observed. Twenty-four of 28 patients with mutations that cause premature truncation of the NF2 protein, schwannomin, present with severe phenotypes. In contrast, all 16 cases from three families with mutations that affect only a single amino acid have mild NF2. These data provide conclusive evidence that a phenotype/genotype correlation exists for certain NF2 mutations.
Asunto(s)
Genes de la Neurofibromatosis 2 , Mutación , Neurofibromatosis 2/clasificación , Adolescente , Adulto , Anciano , Secuencia de Bases , Cartilla de ADN , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neurofibromatosis 2/etiología , Neurofibromatosis 2/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN , Índice de Severidad de la EnfermedadRESUMEN
The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.
Asunto(s)
Neoplasias de la Mama/genética , Mutación , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Anciano , Proteína BRCA2 , Secuencia de Bases , Cartilla de ADN , Femenino , Marcadores Genéticos , Heterocigoto , Humanos , Linfocitos/fisiología , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteína de Retinoblastoma/genética , Eliminación de SecuenciaRESUMEN
The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.
Asunto(s)
Neoplasias de la Mama Masculina/genética , Neoplasias de la Mama/genética , Proteínas de Neoplasias/genética , Mutación Puntual , Eliminación de Secuencia , Factores de Transcripción/genética , Adulto , Edad de Inicio , Anciano , Secuencia de Aminoácidos , Proteína BRCA1 , Proteína BRCA2 , Secuencia de Bases , Canadá , Codón , Análisis Mutacional de ADN , Exones , Familia , Femenino , Francia/etnología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Linaje , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor gene for human breast cancer. It has been shown to reduce the tumorigenicity of breast cancer cell lines in nude mice, and loss of expression of this gene has been shown in primary breast tumors. Furthermore, the human MDGI gene has been mapped to human chromosome 1p32-p35, a common region of deletion in sporadic breast tumors. We have determined the genomic structure of the human MDGI gene from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers approximately 8 kb of genomic DNA and is divided into four exons. In an attempt to identify possible inactivating mutations in the MDGI gene in human breast cancer, we have sequenced all four exons and their surrounding splice junctions in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion containing the MDGI gene. No mutations were found in this analysis. A polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in this study, which resulted in the conversion of a lysine to an arginine residue at codon 53. This variant was present in the constitutional DNA of a further 3/26 women with sporadic breast cancer and 2/90 control individuals (P = 0.20). Despite experimental evidence that MDGI has tumor suppressor activity, our data suggest that mutations in the coding region are uncommon in human breast tumorigenesis.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas Portadoras/genética , Mutación , Secuencia de Bases , Cromosomas Humanos Par 1 , Clonación Molecular , ADN Satélite , Exones , Proteína 3 de Unión a Ácidos Grasos , Proteínas de Unión a Ácidos Grasos , Femenino , Genes Supresores de Tumor , Marcadores Genéticos , Heterocigoto , Humanos , Intrones , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo GenéticoRESUMEN
Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.
Asunto(s)
Genes ras , Repeticiones de Minisatélite , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Adulto , Alelos , Proteína BRCA1 , Secuencia de Bases , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Cartilla de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Datos de Secuencia Molecular , Neoplasias Ováricas/epidemiología , Proto-Oncogenes Mas , Factores de RiesgoRESUMEN
Central nervous system (CNS) tumours are the most common solid tumours in children. Cytogenetic and molecular genetic studies of these neoplasms have previously shown abnormalities of chromosome 17, implicating genes on this autosome in tumorigenesis. To identify mutations in the TP53 tumour suppressor gene (17p13.1), we have sequenced the five highly conserved regions of this gene in 29 mixed paediatric CNS tumors. No mutations were detected by this analysis. In order to identify other candidate disease loci on chromosome 17, we have carried out a detailed deletion mapping analysis using 16 polymorphic DNA markers on 19 of the above tumours and an additional four cases. Abnormalities of chromosome 17 occurred in nine cases (39%), six of which were primitive neuroectodermal tumour (PNET)-medulloblastomas. These findings suggest that it is unlikely that the TP53 gene is directly involved in the development of common paediatric brain tumours. This is in contrast to findings from adult brain and other tumour types. Moreover, the frequency of chromosome 17 aberrations, especially in PNET-medulloblastomas, suggests that other genes on this chromosome contribute to tumourigenesis.
Asunto(s)
Neoplasias Encefálicas/genética , Aberraciones Cromosómicas , Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 17 , Genes p53 , Mutación , Neoplasias de la Médula Espinal/genética , Adolescente , Adulto , Secuencia de Bases , Neoplasias Encefálicas/patología , Niño , Preescolar , Mapeo Cromosómico , Secuencia Conservada , Cartilla de ADN , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Neoplasias de la Médula Espinal/patología , Transcripción GenéticaRESUMEN
The contributions of the early (passive) and late (active) components of ventricular filling have been reported to decrease and increase, respectively, during chick embryo cardiac development. We hypothesized that the observed changes in ventricular filling during early cardiac development results from a decrease in cycle length. We studied the effect of development and cycle length on atrioventricular inflow in 28 chick embryos, Hamilton-Hamburger stages 17, 24, and 26. Cycle length was perturbed (range 240-1040 ms) in ovo by transiently heating or cooling the sinus venosus. Atrioventricular inflow and dorsal aortic velocities were obtained by 20-MHz pulsed Doppler flow-meter and digitally recorded at 500 samples per second. Stroke volume was calculated from dorsal aortic velocity and cross-sectional area. The atrioventricular inflow wave form was integrated and partitioned by area and percentage of total into early (passive) and late (active) components using three methods. Regardless of method, the proportion of filling volume due to the early and late components was cycle length and stage dependent (p < 0.05). The early and late filling volumes were large in the older embryos, and during cycle length decrease (heart rate increase) the early filling volume decrease was greater than the late filling volume decrease. When compared with the percentage of intrinsic heart rate, the percentage of stroke volume due to early filling decreased as heart rate increased and was greater in younger embryos at all heart rates. That due to late filling increased as the percentage of intrinsic heart rate increased. Ventricular filling characteristics are both developmentally determined and cycle length dependent.
Asunto(s)
Embrión de Pollo/fisiología , Frecuencia Cardíaca , Función Ventricular , Animales , DiástoleRESUMEN
Meningiomas are common central nervous system tumours which present usually in the 4th and 5th decades of life. Loss of constitutional heterozygosity on chromosome 22 in 60% of sporadic meningiomas has implied the involvement of a tumour suppressor gene. The neurofibromatosis type 2 gene (NF2), a prime candidate for involvement in meningioma, was screened for point mutations. After examining eight of the 16 known NF2 exons in 151 meningiomas, 24 inactivating mutations were characterized. Significantly, these aberrations were exclusively detected in tumours which lost the other chromosome 22 allele. These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas.