The role of genetic diversity in cancer

Abstract

The role of genetic heterogeneity within neoplasms is increasingly recognized as important for understanding the dynamics of cancer progression, cancer stem cells, and therapeutic resistance, and there is interest in intratumoral heterogeneity measurements as potential biomarkers for risk stratification. In this issue of the JCI, Park et al. characterize this genetic diversity in carcinoma in situ and in invasive regions from 3 types of human breast cancers and lay the groundwork for translation of these measures to the clinic.

Figure 1. For neoplasms maintained by stem cells, somatic evolution will be dominated by evolution within the stem cell compartment.

Here, the blue stem cell subclone may have a competitive advantage and expand relative to the other stem cell subclones. Thus, the cancer stem cell hypothesis and the somatic evolutionary theory of cancer are not mutually exclusive. Because the non–stem cells are, by definition, not self-renewing, they are evolutionary dead ends. However, the genetic diversity in the non–stem cell compartment should reflect the genetic diversity in the stem cell compartment, with the exception of differences in the proliferation rates of the different non–stem cell subclones, which might slightly skew their frequencies relative to the stem cell pool, and rare genetic alterations that occur during the few cell divisions that separate a non–stem cell from its stem cell ancestor. If neoplastic non–stem cells can revert to a stem cell phenotype, then the evolutionary dynamics become more complex and some of the non–stem cells may not be evolutionary dead ends. The results reported by Park et al. in this issue of the JCI (11) suggest that CD44 and CD24 do not distinguish between stem cells and non–stem cells in breast cancer.