RESUMEN
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Asunto(s)
Neoplasias Cerebelosas/terapia , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Meduloblastoma/terapia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Selección Genética/efectos de los fármacos , Animales , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/radioterapia , Neoplasias Cerebelosas/cirugía , Células Clonales/patología , Irradiación Craneoespinal , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Drosophila melanogaster/citología , Drosophila melanogaster/genética , Femenino , Genoma Humano/genética , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/radioterapia , Meduloblastoma/cirugía , Ratones , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia/terapia , Radioterapia Guiada por Imagen , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases É and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , ADN Polimerasa III/genética , ADN Polimerasa II/genética , Replicación del ADN/genética , Modelos Moleculares , Exodesoxirribonucleasas/genética , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal/genética , Humanos , Repeticiones de Microsatélite/genética , Linaje , Proteínas de Unión a Poli-ADP-Ribosa , Schizosaccharomyces/genética , Análisis de Secuencia de ADNRESUMEN
We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.
