RESUMEN
We have examined the developmental expression of the murine breast and ovarian cancer susceptibility gene, Brca1, to investigate its role in the control of cell growth and differentiation. Specifically, we have analysed Brca1 expression during embryonic development, in adult tissues, and during postnatal mammary gland development, particularly in response to ovarian hormones. Our results suggest that Brca1 is expressed in rapidly proliferating cell types undergoing differentiation. In the mammary gland, Brca1 expression is induced during puberty, pregnancy, and following treatment of ovariectomized animals with 17 beta-estradiol and progesterone. These observations imply that Brca1 is involved in the processes of proliferation and differentiation in multiple tissues, notably in the mammary gland in response to ovarian hormones.
Asunto(s)
Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión Génica , Glándulas Mamarias Animales/metabolismo , Proteínas de Neoplasias/biosíntesis , Factores de Transcripción/biosíntesis , Animales , Proteína BRCA1 , Secuencia de Bases , División Celular/genética , Células Cultivadas , Desarrollo Embrionario y Fetal , Epitelio/metabolismo , Estradiol/farmacología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hibridación in Situ , Lactancia , Masculino , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/embriología , Glándulas Mamarias Animales/crecimiento & desarrollo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Datos de Secuencia Molecular , Proteínas de Neoplasias/genética , Oligonucleótidos Antisentido , Especificidad de Órganos , Ovariectomía , Paridad , Embarazo , Progesterona/farmacología , Maduración Sexual , Factores de Transcripción/genéticaRESUMEN
The BRCA1 gene on chromosome 17q21 is responsible for an autosomal dominant syndrome of increased susceptibility to breast and ovarian cancer but no somatic mutations in tumours have yet been described. To study the potential role of BRCA1 in sporadic carcinogenesis, we analysed the genomic DNA of tumour and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the single-strand conformation polymorphism technique. We now describe somatic mutations in the DNA of four tumours which also had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers.
Asunto(s)
Mutación , Oncogenes , Neoplasias Ováricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 17 , ADN de Neoplasias/genética , Femenino , Genes Dominantes , Genes Supresores de Tumor , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , 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
The breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, was recently isolated. Mutations in BRCA2 are thought to account for as much as 35% of all inherited breast cancer as wall as a proportion of inherited ovarian cancer. Many BRCA2-linked families also contain cases of male breast cancer. We have analysed germline DNA from 50 males with breast cancer (unselected for family history) and 26 individuals from site-specific female breast and breast-ovarian cancer families for mutations in BRCA2. All 17 breast-ovarian cancer families have been screened for BRCA1 coding region mutations and none were detected. Conformation-sensitive gel electrophoresis (CSGE) analysis of PCR-amplified DNA followed by direct sequencing was used to detect sequence variants. Three of eleven individuals carry the same mutation, all are of Ashkenazi Jewish descent, supporting the observation by Neuhausen et al. in this issue that there is a common mutation in this population. Eleven truncating mutations and nine polymorphisms were identified -- all were coding region variants. No loss-of-transcript mutations were identified in the sixteen samples for which this analysis was possible. Seven of the nine disease-associated mutations were detected in the 50 men with breast cancers; for thus in our series, BRCA2 mutations account for 14% of male breast cancer, all but one of which had a family history of male and/or female breast cancer.
Asunto(s)
Neoplasias de la Mama Masculina/genética , Neoplasias de la Mama/genética , Mutación , Proteínas de Neoplasias/genética , Polimorfismo Genético , Factores de Transcripción/genética , Proteína BRCA2 , Secuencia de Bases , ADN/sangre , ADN/química , ADN/aislamiento & purificación , Análisis Mutacional de ADN , Cartilla de ADN , Susceptibilidad a Enfermedades , Exones , Familia , Femenino , Marcadores Genéticos , Humanos , Masculino , Datos de Secuencia Molecular , Neoplasias Ováricas/genética , Reacción en Cadena de la PolimerasaRESUMEN
Breast cancer results from genetic and environmental factors leading to the accumulation of mutations in essential genes. Genetic predisposition may have a strong, almost singular effect, as with BRCA1 and BRCA2, or may represent the cumulative effects of multiple low-penetrance susceptibility alleles. Here we review high- and low-penetrance breast-cancer-susceptibility alleles and discuss ongoing efforts to identify additional susceptibility genes. Ultimately these discoveries will lead to individualized breast cancer risk assessment and a reduction in breast cancer incidence.
Asunto(s)
Neoplasias de la Mama/genética , Proteína BRCA2 , Femenino , Genes BRCA1 , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Proteínas de Neoplasias/genética , Factores de Transcripción/genéticaRESUMEN
A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation-associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively) by array-based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1-36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2-24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRAS(wt/wt) tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations.
Asunto(s)
Aberraciones Cromosómicas , Dosificación de Gen , Genes ras , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Línea Celular Tumoral , Distribución de Chi-Cuadrado , Humanos , Mutación , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de SeñalRESUMEN
A high-frequency radar remote-sensing system for measuring and mapping near-surface ocean currents in coastal waters has been analyzed and described. A transportable prototype version of the system was designed, constructed, and tested. With two units operating tens of kilometers apart, the currents were mapped in near real time at a grid of points 3 by 3 km covering areas exceeding 2000 kM(2), out to a distance of about 70 km from the shore. Preliminary estimates of the precision of current velocity measurements show it to be better than 30 cm/sec.
RESUMEN
C-myb, the normal cellular homolog of the retroviral transforming gene v-myb, encodes a nuclear, transcriptional regulatory protein (p75c-myb). C-myb is involved in regulating normal human hematopoiesis, and inhibits dimethyl sulfoxide-induced differentiation of Friend murine erythroleukemia (F-MEL) cells. An alternately spliced c-myb mRNA encodes a truncated version of p75c-myb (mbm2) that includes the DNA binding region and nuclear localization signal present in the c-myb protein, but does not contain the transcriptional regulatory regions. Constitutive expression of mbm2, in contrast to c-myb, here resulted in enhanced differentiation of F-MEL cells. These data suggest that the c-myb protooncogene encodes alternately spliced mRNA species with opposing effects on differentiation.
Asunto(s)
Eritrocitos/citología , Proteínas Proto-Oncogénicas/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Clonación Molecular , Dimetilsulfóxido/farmacología , Biblioteca de Genes , Leucemia Eritroblástica Aguda , Leucemia Linfoide , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-myb , Empalme del ARN , ARN Mensajero , Transfección , Células Tumorales CultivadasRESUMEN
The cancer susceptibility genes BRCA1 and BRCA2 appear to be responsible for virtually all hereditary breast ovarian families, and a smaller subset of hereditary site-specific breast cancer families. Fortunately, effective strategies have been developed to reduce the risk for the development of breast and ovarian cancer in women with BRCA1/2 mutations, making genetic testing for these mutations an important part of the management at women with a strong family history of these diseases. Here, we review the current evidence for risk reduction strategies and outline future research directions.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Tamización de Portadores Genéticos , Mutación , Neoplasias Ováricas/genética , Neoplasias de la Mama/prevención & control , Femenino , Humanos , Neoplasias Ováricas/prevención & control , Conducta de Reducción del RiesgoRESUMEN
The effects of tumor necrosis factor (TNF) on the regulation of macrophage-specific colony stimulating factor (CSF-1) gene expression have been studied in HL-60 cells during monocytic differentiation. CSF-1 transcripts were undetectable in uninduced HL-60 cells, reached maximal levels by 3 h of exposure to TNF, and returned to that of control cells by 24 h. Transcriptional run-on analysis demonstrated that exposure to TNF stimulated the rate of CSF-1 gene transcription by 6.4-fold. The combination of a protein synthesis inhibitor, cycloheximide, and TNF increased levels of CSF-1 mRNA compared with treatment by TNF alone. We also studied the signal transduction mechanisms responsible for regulating TNF-induced CSF-1 mRNA levels. Both 4-bromophenacyl bromide and quinacrine, inhibitors of phospholipase A2 activity, blocked TNF-induced increases in CSF-1 transcripts in a concentration-dependent manner, while caffeic acid and nordihydroguaiaretic acid, inhibitors of the 5-lipoxygenase pathway, had no detectable effect on induction of CSF-1 RNA. PGE2 or dibutyryl cAMP treatment of HL-60 cells in the presence of TNF blocked the expression of CSF-1 mRNA in a dose-dependent manner. These findings suggest that the increase in CSF-1 RNA observed during TNF treatment is regulated, at least in part, by both transcriptional and posttranscriptional mechanisms, and that PGE2 and cAMP regulate transcriptional activation of the CSF-1 gene by TNF.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Factores Estimulantes de Colonias/genética , Regulación de la Expresión Génica/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Acetofenonas/farmacología , Ácido Araquidónico , Cicloheximida/farmacología , Dinoprostona/farmacología , Humanos , Leucemia Promielocítica Aguda/metabolismo , Factor Estimulante de Colonias de Macrófagos , Células Tumorales CultivadasRESUMEN
Inherited mutations in BRCA1 confer susceptibility to breast and ovarian neoplasms. However, the function of BRCA1 and the role of BRCA1 in noninherited cancer remain unknown. Characterization of alternately spliced forms of BRCA1 may identify functional regions; thus, we constructed expression vectors of BRCA1 and a splice variant lacking exon 11, designated BRCA1 delta 672-4095. Immunofluorescence studies indicate nuclear localization of BRCA1 but cytoplasmic localization of BRCA1 delta 672-4095. Two putative nuclear localization signals (designated NLS1 and NLS2) were identified in exon 11; immunofluorescence studies indicate that only NLS1 is required for nuclear localization. RNA analysis indicates the expression of multiple, tissue-specific forms of BRCA1 RNAs; protein analysis with multiple antibodies suggests that at least three BRCA1 isoforms are expressed, including those lacking exon 11. The results suggest that BRCA1 is a nuclear protein and raise the possibility that splicing is one form of regulation of BRCA1 function by alteration of the subcellular localization of expressed proteins.
Asunto(s)
Empalme Alternativo , Proteína BRCA1/análisis , Núcleo Celular/química , Genes BRCA1/genética , Células 3T3 , Animales , Proteína BRCA1/química , Proteína BRCA1/genética , Células COS , Citoplasma/química , ADN Complementario/genética , Exones/genética , Humanos , Ratones , Peso Molecular , ARN Mensajero/análisis , Eliminación de SecuenciaRESUMEN
BACKGROUND: Kabuki (Niikawa-Kuroki) syndrome comprises a characteristic facial appearance, cleft palate, congenital heart disease, and developmental delay. Various cytogenetically visible chromosomal rearrangements have been reported in single cases, but the molecular genetic basis of the condition has not been established. A recent report described a duplication of 8p22-p23.1 in 13/13 patients. OBJECTIVE: To determine the frequency of an 8p duplication in a cohort of patients with Kabuki syndrome. METHODS: An 8p duplication was sought using two independent methods--array based comparative genomic hybridisation (aCGH) and fluorescence in situ hybridisation (FISH)--in 15 patients with a definitive clinical diagnosis of Kabuki syndrome. RESULTS: No evidence for a duplication of 8p was obtained by FISH or aCGH in any of the 15 patients. CONCLUSIONS: 8p22-p23.1 duplication may not be a common mechanism for Kabuki syndrome. Another genetic abnormality may be responsible for the aetiology in many patients.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 8 , Duplicación de Gen , Niño , Cromosomas Artificiales Bacterianos , Estudios de Cohortes , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Hibridación de Ácido Nucleico , Reproducibilidad de los ResultadosRESUMEN
Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estrógenos/efectos adversos , Predisposición Genética a la Enfermedad , Mutación , Consumo de Bebidas Alcohólicas/efectos adversos , Animales , Arilamina N-Acetiltransferasa/genética , Citocromo P-450 CYP1A1/genética , Conducta Alimentaria , Femenino , Efecto Fundador , Genes BRCA1/genética , Genes Supresores de Tumor/genética , Glutatión Transferasa/genética , Humanos , Traumatismos por Radiación/complicaciones , Radioterapia/efectos adversos , Ratas , Factores de Riesgo , SíndromeRESUMEN
BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Genes BRCA1/genética , Mutación , Ovariectomía , Factores de Edad , Neoplasias de la Mama/prevención & control , Estudios de Casos y Controles , Terapia de Reemplazo de Estrógeno , Femenino , Heterocigoto , Humanos , Oportunidad Relativa , Sistema de Registros , Riesgo , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
BACKGROUND: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. METHODS: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. RESULTS: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. CONCLUSIONS: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Heterocigoto , Mutación , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/prevención & control , Fumar , Estudios de Casos y Controles , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , RiesgoRESUMEN
The present studies were aimed at determining if the use of a cell culture medium that supports proliferation of human mammary epithelial cells of the luminal lineage would allow routine isolation of breast cancer cells from primary and metastatic tumor specimens. Results obtained with mammary epithelial cells derived from reduction mammoplasty specimens and primary breast carcinomas indicated that growth of cells on type I collagen-coated dishes in Ham's F-12 medium supplemented with insulin, hydrocortisone, epidermal growth factor, cholera toxin, and 5% fetal bovine serum resulted in the growth and serial passage of cells that stained positively for the luminal cell marker cytokeratin 19. By contrast, growth of mammary epithelial cells in a growth factor-supplemented serum-free medium resulted in the emergence of mammary epithelial cell colonies that were uniformly negative for keratin 19. Filter isolation methods were used to isolate individual keratin-19-positive colonies from primary cultures derived from breast cancer specimens. All of the luminal mammary epithelial cells isolated from breast cancer tissues expressed characteristics of normal cells. Keratin-19-positive colonies isolated from several different tumors all grew rapidly for 30 to 60 days in culture and then senesced. Cells were isolated from one tumor that was known to have undergone a loss of heterozygosity at a specific locus in the p53 gene. All colonies isolated from this specimen contained both p53 alleles, which was consistent with their origin from normal luminal cells. Cells were also isolated from one tumor in which the c-erbB2 protein was drastically overexpressed in the neoplastic cells. Once again, keratin-19-positive colonies isolated from this tumor did not overexpress the c-erbB-2 protein. Experiments were then performed with cells derived from pleural effusions and metastatic lymph nodes. Results obtained with these specimens indicated that the growth conditions that support the growth of normal luminal mammary epithelial cells do not support the growth of neoplastic cells. However, the omission of cholera toxin, epidermal growth factor, and type I collagen substratum resulted in the isolation of two long-term cell lines. Both cell lines have population doubling times of approximately 100 h, are hyperdiploid, and stain positively for cytokeratin 19. Thus, culture conditions that support the growth of normal luminal mammary epithelial cells do not, in general, support the growth of breast cancer cells.
Asunto(s)
Neoplasias de la Mama/patología , Mama/citología , Secuencia de Bases , División Celular/fisiología , Células Cultivadas , Medios de Cultivo , Técnicas de Cultivo , Células Epiteliales , Femenino , Humanos , Metástasis Linfática , Datos de Secuencia Molecular , Fenotipo , Derrame Pleural/citología , Derrame Pleural/patología , Células Tumorales CultivadasRESUMEN
Germline mutations of the BRCA1 tumor suppressor gene on chromosome 17q are involved in a significant fraction of hereditary breast and ovarian cancers. Allelic deletions that include the BRCA1 locus are common in breast and ovarian cancers, implying that somatic mutations of this gene may play an important role in the more common sporadic forms of these tumors as well. The recent cloning of BRCA1 allows direct testing of this hypothesis. A combination of single strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice donor and acceptor regions of BRCA1 for mutations in 115 unselected cases of epithelial ovarian carcinoma. Seven mutations were identified, all of which were present in the germlines of patients with remarkable family or medical histories of breast and/or ovarian cancer. Eighty-nine of these tumors were examined for loss of heterozygosity in the BRCA1 region of chromosome 17q, and 67% of the tumors studied exhibited allelic deletions that included this region. These data are consistent with the hypothesis that BRCA1 mutations are involved in the etiology of hereditary ovarian carcinomas but occur rarely in sporadic tumors, and that the frequent allelic loss on chromosome 17q in this cancer type reflects the involvement of an additional tumor suppressor gene(s).
Asunto(s)
Mutación de Línea Germinal , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Adulto , Anciano , Alelos , Proteína BRCA1 , Secuencia de Bases , Neoplasias de la Mama/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Exones , Femenino , Mutación del Sistema de Lectura , Eliminación de Gen , Genes Relacionados con las Neoplasias/genética , Humanos , Intrones , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.
Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Proteínas de Neoplasias/genética , Historia Reproductiva , Factores de Transcripción/genética , Adulto , Anciano , Alelos , Proteína BRCA2 , Neoplasias de la Mama/patología , Femenino , Frecuencia de los Genes , Genotipo , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Coactivador 3 de Receptor Nuclear , Factores de Riesgo , Repeticiones de Trinucleótidos/genéticaRESUMEN
Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.