RESUMEN
Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.
Asunto(s)
Hibridación Genómica Comparativa/métodos , Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , Proteínas Supresoras de Tumor/genética , Animales , Sitios de Unión/genética , Línea Celular Tumoral , Elementos Transponibles de ADN/genética , Femenino , Genómica/métodos , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutagénesis Insercional , Mutación , Proteína Homeótica Nanog , Neoplasias/metabolismo , Neoplasias/patología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Especificidad de la Especie , Células Madre/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The elucidation of the human and mouse genome sequence and developments in high-throughput genome analysis, and in computational tools, have made it possible to profile entire cancer genomes. In parallel with these advances mouse models of cancer have evolved into a powerful tool for cancer gene discovery. Here we discuss the approaches that may be used for cancer gene identification in both human and mouse and discuss how a cross-species 'oncogenomics' approach to cancer gene discovery represents a powerful strategy for finding genes that drive tumourigenesis.
Asunto(s)
Genes Relacionados con las Neoplasias , Neoplasias/genética , Animales , Hibridación Genómica Comparativa , Elementos Transponibles de ADN , Epigénesis Genética , Dosificación de Gen , Ingeniería Genética , Humanos , Ratones , Mutagénesis InsercionalRESUMEN
p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19(ARF)-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Redes Reguladoras de Genes , Genes Supresores de Tumor , Neoplasias/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular Tumoral , Clonación Molecular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Genes p53 , Genómica/métodos , Humanos , Ratones , Ratones Noqueados , Mutagénesis Insercional , Neoplasias/metabolismo , Análisis de Secuencia de ADNRESUMEN
High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (P(trend) = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of > or =50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers.
