Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy

Abstract

BackgroundChromosomal aneuploidy, that is to say the gain or loss of chromosomes, is the most common abnormality in cancer. While certain aberrations, most commonly translocations, are known to be strongly associated with specific cancers and contribute to their formation, most aberrations appear to be non-specific and arbitrary, and do not have a clear effect. The understanding of chromosomal aneuploidy and its role in tumorigenesis is a fundamental open problem in cancer biology.ResultsWe report on a systematic study of the characteristics of chromosomal aberrations in cancers, using over 15,000 karyotypes and 62 cancer classes in the Mitelman Database. Remarkably, we discovered a very high co-occurrence rate of chromosome gains with other chromosome gains, and of losses with losses. Gains and losses rarely show significant co-occurrence. This finding was consistent across cancer classes and was confirmed on an independent comparative genomic hybridization dataset of cancer samples. The results of our analysis are available for further investigation via an accompanying website.ConclusionsThe broad generality and the intricate characteristics of the dichotomy of aneuploidy, ranging across numerous tumor classes, are revealed here rigorously for the first time using statistical analyses of large-scale datasets. Our finding suggests that aneuploid cancer cells may use extra chromosome gain or loss events to restore a balance in their altered protein ratios, needed for maintaining their cellular fitness.

Single-chromosome Gains Commonly Function as Tumor Suppressors

“…It may be the case that the gain of mChr2 and mChr19 in cells expressing LTa is one such sweet spot, and that these aneuploidy sweet spots represent frequently observed karyotypes in cancer. Consistent with this notion, many distinct chromosome CNAs are observed together in the same tumors more often than expected by chance (Ozery-Flato et al, 2011). For instance, tumors that have gained an extra copy of hChr7 are significantly more likely to have also gained an extra copy of hChr17, while loss of hChr7 is correlated with loss of hChr17 (Ozery-Flato et al, 2011).…”

“…For example, trisomy of chromosome 21 predisposes individuals to leukemia (Seewald et al, 2012), and gain of chromosome 21 is a common occurrence in sporadic leukemia (Loncarevic et al, 1999; Ozery-Flato et al, 2011), but trisomy of chromosome 21 appears to protect against the development of many other cancer types, including breast, lung, and prostate cancers (Nižetić and Groet, 2012). Similarly, a recent report suggests that, while aneuploidy is typically detrimental to cell fitness, under certain conditions, such as hypoxia or chemotherapy treatment, aneuploid cells may proliferate better than euploid cells do (Rutledge et al, 2016).…”

“…First, individuals with Down syndrome (trisomy 21) frequently develop pediatric leukemia, suggesting a clear link between the gain of chromosome 21 and leukemogenesis (Seewald et al, 2012). Second, many human cancers exhibit recurrent aneuploidies (Ozery-Flato et al, 2011; Zack et al, 2013), and computational modeling has suggested that these patterns of chromosomal alterations reflect an evolutionary process in which cancer cells increase the copy number of loci encoding oncogenes and decrease the copy number of loci encoding tumor suppressors (Davoli et al, 2013). Finally, genetically engineered mice that harbor alleles that cause chromosomal instability (CIN) typically develop tumors at accelerated rates (Li et al, 2009; Michel et al, 2001; Park et al, 2013; Sotillo et al, 2007, 2010), particularly when combined with mutations in the p53 tumor suppressor (Li et al, 2010).…”

DYRK1A in Down syndrome: an oncogene or tumor suppressor?

“…Chromosomal aneuploidies are commonly detected in cancer (22). Thus, the answers to these questions as well as additional studies of the role of cT21 in the leukemias associated with DS may have general implications for understanding the oncogenic mechanisms of acquired chromosomal aneuploidies.…”

Single-cell analysis of aneuploidy events using yeast whole chromosome painting probes (WCPPs)

“…Indeed, aneuploidy is the most common feature of cancer cells. Aneuploidy is speculated to affect approximately 90% of solid tumours (Ozery-Flato et al, 2011;Weaver and Cleveland, 2006). Nevertheless, the impact of aneuploidy on fitness is context-specific (Pavelka et al, 2010a).…”