RESUMEN
Recent genomewide association studies have found multiple genetic variants on chromosome 8q24 that are significantly associated with an increased susceptibility to prostate, colorectal, and breast cancer. These risk loci are located in a "gene desert," a few hundred kilobases telomeric to the Myc gene. To date, the biological mechanism(s) underlying these associations remain unclear. It has been speculated that these 8q24 genetic variant(s) might affect Myc expression by altering its regulation or amplification status. Here, we show that multiple enhancer elements are present within this region and that they can regulate transcription of Myc. We also demonstrate that one such enhancer element physically interacts with the Myc promoter via transcription factor Tcf-4 binding and acts in an allele specific manner to regulate Myc expression.
Asunto(s)
Cromosomas Humanos Par 8/genética , Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Inmunoprecipitación de Cromatina , Biología Computacional , Cartilla de ADN/genética , Humanos , Luciferasas , Datos de Secuencia Molecular , Neoplasias/metabolismo , Factor de Transcripción 4 , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
Rapid technical advances in DNA sequencing and genome-wide association studies are driving the discovery of the germline and somatic mutations that are present in different cancers. Mutations in genes involved in cellular signaling are common, and often shared by tumors that arise in distinct anatomical locations. Here we review the most important molecular changes in different cancers from the perspective of what should be analyzed on a routine basis in the clinic. The paradigms are EGFR mutations in adenocarcinoma of the lung that can be treated with gefitinib, KRAS mutations in colon cancer with respect to treatment with EGFR antibodies, and the use of gene-expression analysis for ER-positive, node-negative breast cancer patients with respect to chemotherapy options. Several other examples in both solid and hematological cancers are also provided. We focus on how disease subtypes can influence therapy and discuss the implications of the impending molecular diagnostic revolution from the point of view of the patients, clinicians, and the diagnostic and pharmaceutical companies. This paradigm shift is occurring first in cancer patient management and is likely to promote the application of these technologies to other diseases.