Chromosomal instability (CIN), an increased rate of chromosome segregation errors during mitosis, is a hallmark of cancer cells. CIN leads to karyotype differences between cells and thus large-scale heterogeneity among individual cancer cells; therefore, it plays an important role in cancer evolution. Studying CIN and its consequences is technically challenging, but various technologies have been developed to track karyotype dynamics during tumorigenesis, trace clonal lineages and link genomic changes to cancer phenotypes at single-cell resolution. These methods provide valuable insight not only into the role of CIN in cancer progression, but also into cancer cell fitness. In this Cell Science at a Glance article and the accompanying poster, we discuss the relationship between CIN, cancer cell fitness and evolution, and highlight techniques that can be used to study the relationship between these factors. To that end, we explore methods of assessing cancer cell fitness, particularly for chromosomally unstable cancer.

We identify critical conserved and mutated genes through a theoretical model linking a gene’s fitness contribution to its observed mutational frequency in a clinical cohort. “Passenger” gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected. Non-synonymous mutations in essential genes reduce fitness and are eliminated by natural selection resulting in lower prevalence than expected. We apply this “evolutionary triage” principle to TCGA data from EGFR-mutant, KRAS-mutant, and NEK (non-EGFR/KRAS) lung adenocarcinomas. We find frequent overlap of evolutionarily selected non-synonymous gene mutations among the subtypes suggesting enrichment for adaptations to common local tissue selection forces. Overlap of conserved genes in the LUAD subtypes is rare suggesting negative evolutionary selection is strongly dependent on initiating mutational events during carcinogenesis. Highly expressed genes are more likely to be conserved and significant changes in expression (>20% increased/decreased) are common in genes with evolutionarily selected mutations but not in conserved genes. EGFR-mut cancers have fewer average mutations (89) than KRAS-mut (228) and NEK (313). Subtype-specific variation in conserved and mutated genes identify critical molecular components in cell signaling, extracellular matrix remodeling, and membrane transporters. These findings demonstrate subtype-specific patterns of co-adaptations between the defining driver mutation and somatically conserved genes as well as novel insights into epigenetic versus genetic contributions to cancer evolution.