RESUMEN
Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (-1381C>T, -244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53-1.00, 0.46-0.95 and 0.39-0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.
Asunto(s)
Neoplasias de la Mama/genética , Variación Genética , Polimorfismo de Nucleótido Simple , Telómero/genética , Adulto , Anciano , Proteínas Portadoras/genética , Estudios de Casos y Controles , ADN de Neoplasias , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Proteínas Nucleares/genética , Oportunidad Relativa , Polonia , Proteínas de Unión al ARN , Medición de Riesgo , Factores de Riesgo , Complejo Shelterina , Proteínas Similares a la Proteína de Unión a TATA-Box/genética , Telomerasa/genética , Proteínas de Unión a Telómeros/genética , Proteína 2 de Unión a Repeticiones TeloméricasRESUMEN
Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics (histopathologic type, grade, size, and nodal status) in a population-based case-control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (> 2 cm) tumours (odds ratios (95% confidence intervals) 1.19 (1.07-1.33) for a 5-year increase in age), but not smaller tumours (P for heterogeneity adjusting for other tumour features (Phet) = 0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68-0.86) per additional birth; Phet = 0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66-3.15)) and grade 1 (3.36 (2.22-5.08)) tumours (Phet = 0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types (Phet = 0.63 for ductal vs lobular). Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women (Phet = 0.05 and 0.0001, respectively). None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts.
Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Modelos Estadísticos , Invasividad Neoplásica , Oportunidad Relativa , Polonia/epidemiología , Vigilancia de la Población , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Skewed X chromosome inactivation may be more common in women with epithelial ovarian cancer and early-onset breast cancer. We tested this hypothesis in a group of 235 breast cancer patients and 253 controls (mean age 45.8 years) from a larger population based case control study. METHODS: We measured X chromosome inactivation with the AR gene assay in lymphocyte DNA digested with the methylation specific enzyme HpaII. We judged skewness using an adjusted measure (relative to the undigested sample) with a cut point of 75%, and an unadjusted measure where skewed was defined as > 90% of the signal from one allele in the HpaII digested sample. RESULTS: There were no significant differences in any of the skewing measures between cases and controls. Using the adjusted skewing measure among pre-menopausal subjects under the age of 50, 14% of cases versus 11% of controls were skewed, OR = 1.2, 95% CI 0.6 to 2.3; using the unadjusted measure, OR = 0.9, 95% CI 0.4 to 2.0. CONCLUSIONS: While we cannot rule out a subtle difference of approximately twofold or less, we have failed to find a significant difference in the prevalence of skewed X chromosome inactivation in younger women with breast cancer compared to controls.