Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers.

摘要: Human tumors show a high level of genetic heterogeneity, but the processes that influence timing and route metastatic dissemination subclones are unknown. Here we have used whole-exome sequencing 103 matched benign, malignant skin from genetically heterogeneous mice to demonstrate most metastases disseminate synchronously primary tumor, supporting parallel rather than linear evolution as predominant model metastasis. Shared mutations between carcinomas their distinct A-to-T signature initiating carcinogen dimethylbenzanthracene, non-shared primarily G-to-T, associated with oxidative stress. The existence either did or not metastasize in same host animal suggests there tumor-intrinsic factors seeding. We also importance germline polymorphisms determining allele-specific mutations, identify somatic alterations specifically related initiation carcinogenesis by Hras Kras mutations. Mouse mimic heterogeneity human cancers can aid our understanding clonal metastasis provide realistic for testing novel therapies.