Fast somatic evolution creates heterogeneity in metastatic tumors

Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

By Marco Gerlinger, et al.in   New Engl J Med 2012; 366:883-892March 8, 2012 (Not open access)

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Abstract: Large-scale sequencing analyses of solid cancers have identified extensive heterogeneity between individual tumors.1-6 Genetic intratumor heterogeneity has also been shown7-15 and can contribute to treatment failure and drug resistance. Intratumor heterogeneity may have important consequences for personalized-medicine approaches that commonly rely on single tumor-biopsy samples to portray tumor mutational landscapes. Studies comparing mutational profiles of primary tumors and associated metastatic lesions16,17 or local recurrences18 have provided evidence of intratumor heterogeneity at nucleotide resolution. Intratumor heterogeneity within primary tumors and associated metastatic sites has not been systematically characterized by next-generation sequencing. We applied exome sequencing, chromosome aberration analysis, and DNA ploidy profiling to study multiple spatially separated biopsy samples from primary renal-cell carcinomas and associated metastatic sites. We in-vestigated the phenotypic consequences of genetic intratumor heterogeneity and the representation of the tumor genomic landscape by a single tumor-biopsy sample, the current basis for most biomarker discovery and personalized-medicine approaches.