The Impact of Tumor Heterogeneity on Patient Treatment Decisions

The existence of intratumor phenotypic heterogeneity was described a few decades ago, but the biological impact of this clonal diversity remains unknown. In 1976, Peter Nowell stated in Science that tumors arise from a single cell that has undergone several expansion rounds and whose descendants eventually acquire genetic aberrations. He also posited that additional mutational events would drive the behavior of the tumor and determine how the tumor will evolve (1). Nowell proposed the concept that tumor progression is linked to a genetic evolution that follows a Darwinian pattern, thus bringing the notion of tumor evolution to bear on this heterogeneity. Since that time, numerous studies have reported the presence of subpopulations within tumors, and it has been proposed that this clonal diversity could affect tumor evolution by ( a ) providing the diversity on which selection can work and ( b ) modulating progression and resistance through biological interactions between the clones (2).The New England Journal of Medicine recently published a report by Gerlinger et al. entitled “Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing” (3), which evoked the concept of intratumor heterogeneity playing a role in cancer progression and metastasis and in complicating molecularly driven treatment strategies. The authors investigated primary renal carcinomas and their associated metastases via multiregion whole-exome sequencing, chromosome aberration analysis, and DNA ploidy profiling of spatially separated parts of each sample. Immunohistochemical and gene expression analyses were also performed. Their data showed that 63% to 69% of all somatic mutations were not detectable across every tumor region and that a phylogenetic reconstruction of the tumors revealed an evolutionary tumor growth pattern. Additionally, the authors observed different gene expression signatures and divergent allelic-imbalance profiles within some of the tumors. The authors concluded that a single tumor biopsy sample might reveal only a fraction of the genetic …