Genomic Instability in Cancer: Teetering on the Limit of Tolerance

Abstract

Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection, and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared with intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor's burden of genetic aberrations is distributed among coexisting clones, genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor's sensitivity to DNA-damaging therapies. We primarily focus on studies of epithelial-derived solid tumors. Cancer Res; 77(9); 2179-85. ©2017 AACR.

Figure 1. Alternative perspectives on genomic instability and mechanisms that limit genomic instability tolerance

(a) Snapshot of a diploid chromosome’s burden of somatic point mutations (SPMs) and of somatic copy number alterations (SCNAs) at the time of biopsy collection. Mutation burden measured as the total number of SPMs (orange) or as the % chromosome affected by SCNAs (here single-copy gain of one chromosome arm: black). (b) Mutation rate measured as the mutation burden net difference between time points divided by the number of cell generations that took place between those time points. (c–e) Mechanisms that can account for reduced cell fitness due to (c) SPM burden; (d) SCNA burden; (e) SPM- or SCNA rate. Mechanisms include: (c) attack by immune cells, (d) disturbed homeostasis due to gene expression imbalance, impaired mitosis, high energy demands for cell maintenance, (e) mutational meltdown and activation of apoptosis.

Figure 2. Model of DNA damage sensitivity as a function of genomic instability

(a) Tumor-metapopulation fitness (y-axis) is maximal when it consists of subpopulations with intermediate levels of genomic instability (critical range), defined as the proportion of the genome that is altered (x-axis). (b) 50 cells (circles) sampled from a heterogeneous tumor-metapopulation consisting of two subclones of variable genomic instability (colorbar). First round of DNA damaging agents causes a shift in the genomic instability of each subclone, such that one subclone (turquoise) is shifted out of the critical range (now orange), while the other one (dark blue) transitions into a critical range of genomic instability (turquoise). A second round of therapy is needed to push both subpopulations out of the critical range of genomic instability and into the range where genomic instability reduces their fitness.