A ‘DNA replication’ signature of progression and negative outcome in colorectal cancer

Abstract

Colorectal cancer is one of the most frequent cancers worldwide. As the tumor-node-metastasis (TNM) staging classification does not allow to predict the survival of patients in many cases, additional prognostic factors are needed to better forecast their outcome. Genes involved in DNA replication may represent an underexplored source of such prognostic markers. Indeed, accidents during DNA replication can trigger 'replicative stress', one of the main features of cancer from earlier stages onward. In this study, we assessed the expression of 47 'DNA replication' genes in primary tumors and adjacent normal tissues from a homogeneous series of 74 patients. We found that genes coding for translesional (TLS) DNA polymerases, initiation of DNA replication, S-phase signaling and protection of replication forks were significantly deregulated in tumors. We also observed that the overexpression of either the MCM7 helicase or the TLS DNA polymerase POLQ (if also associated with a concomitant overexpression of firing genes) was significantly related to poor patient survival. Our data suggest the existence of a 'DNA replication signature' that might represent a source of new prognostic markers. Such a signature could help in understanding the molecular mechanisms underlying tumor progression in colorectal cancer patients.

A role for DNA polymerase θ in the timing of DNA replication

“…This novel Pol y function may be particularly important within the context of cancer, as high POLQ expression is strongly associated with poor clinical outcome of patients with colon, breast and lung cancers [22][23][24]55,56 . Abnormal temporal control of replication, recently demonstrated in several haematologic malignancies, has been proposed to represent a common mechanism responsible for genomic instability found in cancer cells 57 ; therefore, Pol y overexpression may be of cardinal importance in defining the modified temporal replication programme in cancer cells and may constitute a driving force for chromosomal instability [58][59][60] .…”

“…By conducting large-scale studies of the expression of DNA replication factors in patients with colon, breast and lung cancer, we recently uncovered major alterations in the expression pattern of POLQ, the gene encoding Pol y, and discovered that excess POLQ correlates with genetic instability and poor prognosis [22][23][24] . This is, to our knowledge, the strongest link between a negative clinical outcome and the expression of a DNA polymerase 25 .…”

MCM7 serves as a prognostic marker in diffuse-type gastric adenocarcinoma and siRNA-mediated knockdown suppresses its oncogenic function

“…MCM7 has been reported to be upregulated in many types of cancer and functions as oncogene in muscle- invasive bladder cancer (22), non-small cell lung cancer (23,24), Hodgkin lymphoma (25), prostate cancer (15), liver cancer (26), meningiomas (27), colorectal cancer (28,29), medulloblastoma (30) and oral squamous cell carcinoma (31). By siRNA-mediated knockdown of MCM7 in GAC cell lines, the cell proliferation and invasion were inhibited, thus MCM7 knockdown exerts anti-oncogenic effect in vitro.…”

A Single Residue Unique to DinB-Like Proteins Limits Formation of the Polymerase IV Multiprotein Complex in Escherichia coli

“…Determining how these bacterial enzymes are regulated will allow a better description of the regulation of TLS polymerase activity in other systems. Furthermore, TLS polymerases have been implicated in the evolution of antibiotic resistance in bacteria and cancer in humans (24)(25)(26)(27). Deregulation of TLS polymerases, therefore, has a variety of deleterious consequences in both prokaryotic and eukaryotic organisms.…”