RESUMEN
SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10â»5) and rs828054 (OR = 1.06; p = 1 × 10â»4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10â»6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
Asunto(s)
Carcinoma/genética , Suplementos Dietéticos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Ácido Fólico/uso terapéutico , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Carcinoma/epidemiología , Carcinoma/etiología , Carcinoma/prevención & control , Estudios de Casos y Controles , Dieta/efectos adversos , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Ingestión de Energía , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/dietoterapia , Deficiencia de Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/fisiopatología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Salud Global , Humanos , Análisis Multivariante , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/etiología , Neoplasias Ováricas/prevención & control , Factores de Riesgo , Población BlancaRESUMEN
Recently, the tissue origin of MDA-MB-435 cell line has been the subject of considerable debate. In this study, we set out to determine whether MDA-MB-435-DTP cells shown to express melanoma-specific genes were identical to various other MDA-MB-435 cell stocks worldwide. CGH-microarray, genetic polymorphism genotyping, microsatellite fingerprint analysis and/or chromosomal number confirmed that the MDA-MB-435 cells maintained at the Lombardi Comprehensive Cancer Center (MDA-MB-435-LCC) are almost identical to the MDA-MB-435-DTP cells, and showed a very similar profile to those obtained from the same original source (MD Anderson Cancer Center) but maintained independently (MDA-MB-435-PMCC). Gene expression profile analysis confirmed common expression of genes among different MDA-MB-435-LCC cell stocks, and identified some unique gene products in MDA-MB-435-PMCC cells. RT-PCR analysis confirmed the expression of the melanoma marker tyrosinase across multiple MDA-MB-435 cell stocks. Collectively, our results show that the MDA-MB-435 cells used widely have identical origins to those that exhibit a melanoma-like gene expression signature, but exhibit a small degree of genotypic and phenotypic drift.