RESUMEN
BACKGROUND: Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR). METHODS: The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls. RESULTS: Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9. CONCLUSIONS: These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Leptina/genética , Proteínas de Neoplasias/genética , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Catecol O-Metiltransferasa/genética , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Curva ROC , Receptores Androgénicos/genética , Receptores de Superficie Celular/genética , Receptores de Dopamina D2/genética , Receptores de Estrógenos/genética , Receptores de Leptina , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.