Paradoxical Relationship between Chromosomal Instability and Survival Outcome in Cancer

Abstract

Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumour models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical chromosomal instability in vivo, to gene expression profiles of 2125 breast tumours from 13 published cohorts. Tumours with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor (ER) negative, basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER-negative tumours were associated with improved prognosis relative to tumours with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric and non-small cell lung cancer, with poorest outcome in tumours with intermediate, rather than extreme, CIN70 scores. These results suggest a non-monotonic relationship between gene signature expression and hazard ratio for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER negative breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER-negative breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches.

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

“…In joint analyses with mutation data from KRAS, NRAS, BRAF, PIK3CA, FBXW7 , and TP53 , MSI and the presence or extent of CIN remained the only independent prognostic predictors. Our fi nding of a monotonic association between CIN and poor outcome contrasts with reports in breast, ovarian, gastric, and lung cancers, in which CIN-intermediate tumors had the worst prognosis ( 43 ). In clinical diagnostic practice, we suggest that both MSI and CIN testing are useful for prognostic indication in CRC.…”

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

“…Clinical data indeed show that cancers with a higher load of chromosomal alterations, closer to μ*, respond better to treatments (31)(32)(33). PARP inhibitors, which increase DNA damage in BRCA1/2-positive tumors, may already be curing patients by inducing mutational meltdown (34).…”

“…This general framework for adaptive asexual populations effectively characterizes the dynamics of cancer progression and therapeutic responses. (31,33), whereas patients with very high level of chromosomal instability are most effectively treated. (Lower) This result is well explained by our phase diagrams, where cancers with high mutation rates are susceptible to mutational meltdown, yet paradoxical for all previous evolutionary models of cancer.…”

“…Several recent studies (31)(32)(33) found that patient survival from breast (all subtypes) and ovarian cancer was greatest when tumors harbored exceptionally high levels of chromosomal alterations. These findings are paradoxical for all previous models of cancer (31), where a greater mutation rate always accelerates cancer, yet fully consistent with our model (Fig. 4B).…”

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

“…These results are partially explained by evidence that aneuploidy in eukaryotic cell systems negatively impacts upon cell biological fitness (Torres et al 2007;Williams et al 2008) and excessive CIN may induce autonomous cell lethality (Kops et al 2004; Janssen Birkbak et al 2011). Therefore, it is possible that even in an in vitro environment, as investigated in our study, chromosomally unstable cancer cells could favorably respond to certain chemotherapeutic drugs.…”