RESUMO
Oestrogen exposure has long been considered to be a main risk factor of breast cancer. More recently, interest has also focused on the possible carcinogenic influence from oestrogen metabolites, such as catechol oestrogens. O-methylation, catalysed by Catechol-O-Methyltransferase (COMT), is one pathway by which the potentially carcinogenic catechol oestrogens can be inactivated. The gene coding for COMT protein contains a single-nucleotide polymorphism (SNP), resulting in an amino acid shift Val-->Met, which has been shown to determine high- and low-activity configuration of the enzyme. We hypothesized that the low-activity allele, COMT(Met), may be implicated in early onset breast cancer. In the present case-control study, including 126 young breast cancer patients (Assuntos
Neoplasias da Mama/enzimologia
, Catecol O-Metiltransferase/genética
, Polimorfismo Genético
, Adolescente
, Adulto
, Alelos
, Neoplasias da Mama/genética
, Estudos de Casos e Controles
, Primers do DNA/química
, Feminino
, Humanos
, Linfonodos/patologia
, Metionina/química
, Pessoa de Meia-Idade
, Razão de Chances
, Reação em Cadeia da Polimerase
, Polimorfismo Conformacional de Fita Simples
, Medição de Risco
, Valina/química
RESUMO
Long-term exposure to oestrogens is a well-recognised risk factor for breast cancer, whereas little is known about the influence of polymorphisms of genes involved in oestrogen biosynthesis and metabolism. A candidate, containing a single bp polymorphism, T-->C, (designated, A2 allele), might be the CYP17 gene, which codes for an enzyme involved in oestrogen synthesis. This polymorphism creates an additional Sp1-type promoter site (CCACC box), which has been shown to be associated with increased serum oestrogen levels. We performed a case-control study, to evaluate association of the CYP17 gene polymorphism with risk of breast cancer in young women (younger than 37 years). We found a statistically significant increased risk in carriers of at least 1 A2 allele [odds ratio (OR), 2.0; 95% confidence interval (CI), 1.1-3.5, p = 0.027], and a trend toward a gene-dose effect illustrated by a slightly higher risk for A2-homozygous subjects (OR, 2.8) than for heterozygous women (OR, 1. 9). Furthermore, when we investigated the CYP17 genotype in relation to tumour characteristics, breast cancer patients with 1 or 2 A2 alleles tended to have lower oestrogen receptor levels (risk ratio, 0.70; CI, 0.41-1.2, p = 0.44). Our findings suggest that CYP17 gene polymorphism influences breast carcinogenesis in young women. Int. J. Cancer (Pred. Oncol.) 84:350-353, 1999.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Esteroide 17-alfa-Hidroxilase/genética , Adulto , Fatores Etários , Alelos , Sequência de Bases , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclo Celular , Intervalos de Confiança , Feminino , Triagem de Portadores Genéticos , Humanos , Metástase Linfática , Razão de Chances , Mutação Puntual , Valor Preditivo dos Testes , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Fatores de Risco , Análise de Sobrevida , Suécia/epidemiologiaRESUMO
The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1alpha,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age, <37 years) and a control population (n = 130), revealed no overall association to risk for breast cancer. However, patients without TaqI site (TT genotype) showed a significantly increased risk for lymph node metastasis (relative risk, 1.8, 95% confidence interval, 1.3-2.6). Furthermore, a tendency toward an increased survival was found among estrogen receptor-positive, tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early-onset breast carcinomas.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Antagonistas de Estrogênios/uso terapêutico , Metástase Linfática/genética , Proteínas de Neoplasias/genética , Polimorfismo de Fragmento de Restrição , Receptores de Calcitriol/genética , Tamoxifeno/uso terapêutico , Adulto , Idade de Início , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Desoxirribonucleases de Sítio Específico do Tipo II , Progressão da Doença , Antagonistas de Estrogênios/farmacologia , Feminino , Genótipo , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/química , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Receptores de Estrogênio/análise , Risco , Tamoxifeno/farmacologiaRESUMO
The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age < 37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P = 0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.