Chromosomal Instability
Definition
Chromosomal instability (CIN) is a type of genomic instability involving ongoing errors in chromosome segregation during mitosis, resulting in whole-chromosome or segmental aneuploidy. CIN can also arise from errors of DNA replication and repair (Turajlic et al., 2019). It is distinct from tumors that are clonally aneuploid due to a single missegregation event without ongoing instability — such tumors are homogeneously aneuploid, whereas CIN-driven tumors are heterogeneously (subclonally) aneuploid.
CIN is a defining feature of most solid cancers. As Gerstung et al. (2020) demonstrated, CIN and the copy number alterations it generates affect a greater proportion of the cancer genome than any other mutation type.
Dual Role: Adaptive and Deleterious
CIN has a paradoxical relationship with fitness:
Adaptive potential. CIN provides the raw material for hopeful-monsters — grossly altered clones that may carry multiple adaptive copy-number-alterations simultaneously. It enables rapid phenotypic exploration through large-scale karyotypic change (Turajlic et al., 2019).
Fitness cost. Excessive CIN is lethal. In a pan-cancer analysis of >2,000 samples, only moderate CIN (>25% and <75%) was associated with decreased survival; excessive CIN conferred improved prognosis, consistent with a fitness cost that negates the selective advantage of karyotypic heterogeneity (Turajlic et al., 2019). As Turajlic et al. note, “low levels of aneuploidy may be tumour protective but…the genome-destabilising effects of aneuploidy are tumour-promoting under certain growth conditions” (p. 406).
This creates selection for a “just-right” level of CIN — enough to generate adaptive diversity, but not so much that it causes cell-autonomous lethality.
CIN and Metastasis
CIN is strongly associated with metastatic competence. In TRACERx Renal, the critical difference between metastasis-competent and non-metastasizing clones was the degree of aneuploidy and chromosome complexity. Specific CNAs — loss of 9p and loss of 14q — were enriched in metastasizing clones, while no evidence of selection for small-scale SNV mutations was found (Turajlic et al., 2019).
CIN and Clinical Outcomes
In TRACERx Lung, CIN conferred an increased risk of recurrence and death independently of known predictive markers (Jamal-Hanjani et al., 2017, cited in Turajlic et al., 2019). CIN is also linked to resistance to chemotherapy and to CTLA4 and PD1 immune checkpoint inhibitors (Turajlic et al., 2019).
CIN and Immune Evasion
CIN can lead to subclonal loss of heterozygosity in HLA genes, facilitating immune escape. In NSCLC, pervasive evidence of positive selection was found for HLA LOH events, which allow tumors to accumulate subclonal neo-antigens without triggering immune clearance (McGranahan et al., 2017, cited in Turajlic et al., 2019).