Abstract
Oncogene activation is an established driver of tumorigenesis. An apparently inevitable consequence of oncogene activation is the generation of DNA replication stress (RS), a feature common to most cancer cells. RS, in turn, is a causal factor in the development of chromosome instability (CIN), a near universal feature of solid tumors. It is likely that CIN and RS are mutually reinforcing drivers that not only accelerate tumorigenesis, but also permit cancer cells to adapt to diverse and hostile environments. This article reviews the genetic changes present in cancer cells that influence oncogene-induced RS and CIN, with a particular emphasis on regions of the human genome that show enhanced sensitivity to the destabilizing effects of RS, such as common fragile sites. Because RS exists in a wide range of cancer types, we propose that the proteins involved counteracting this stress are potential biomarkers for indicating the degree of RS in cancer specimens. To test this hypothesis, we conducted a pilot study to validate whether some of proteins that are known from in vitro studies to play an essential role in the RS pathway could be suitable as a biomarker. Our results indicated that this is possible. With this review and pilot study, we aim to accelerate the development of a biomarker for analysis of RS in tumor biopsy specimens, which could ultimately help to stratify patients for different forms of therapy such as the RS inhibitors already undergoing clinical trials.
Highlights
Despite huge advances in our understanding of basic cancer biology, the incidence of cancer worldwide is still rising, and the overall survival rates for patients with advanced cancer are still low
These changes can be observed using conventional karyotyping (Figure 1), but are more evident when using a more advanced method such as spectral karyotyping (SKY), which employs fluorescentlylabeled probes to mark all of the DNA originating from a particular chromosome
We know that many of the structural changes in individual chromosomes are directly responsible for the activation of oncogenes or inactivation of tumor suppressor genes
Summary
Despite huge advances in our understanding of basic cancer biology, the incidence of cancer worldwide is still rising, and the overall survival rates for patients with advanced cancer are still low. A World Health Organization report in 2012 revealed that there were approximately 14 million newly recorded cases of cancer worldwide that year, as well as over 8 million cancer-related deaths [1]. Taking colon cancer cases recorded during 2014-2015 in the USA as an example, those patients with early stage disease (Stage I) had a greater than 90% chance of surviving for more than 5 years after diagnosis. Only around 40% of cases are diagnosed at such an early disease stage. In those cases where the cancer had spread to distant organs (stage IV patient), the 5-year survival dropped dramatically to only around 15%. To significantly improve the survival of cancer patients, progress must be made in targeting those cancers that are at an advanced stage at the point of diagnosis
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