An investigation into DNA damage response and repair genes in cancers of epithelial origin

Abstract

Biomarkers are extremely powerful tools in cancer research. The transition to cancer care under the precision medicine model will require the investigation of novel biomarkers that provide individualized information about the genetic profiles of particular tumours within a given patient. This study sought to investigate DNA damage response and repair genes, which play an important role in maintaining the integrity of the genome, in cancers of epithelial origin. Given their important role, these genes are potential biomarkers that could indicate whether DNA damage is being repaired adequately; where both a lack of or an increase in response could result in cancer. To investigate their potential as biomarkers, two types of DNA damage-related genes were investigated in this study. First, the ability of the status of mismatch repair genes to be used with the status of MAPK pathway oncogenes, as combined biomarkers, to predict survival probability was examined retrospectively using a database from a rural population in New Brunswick, Canada. Both Kaplan-Meier survival analyses and Cox Proportional Hazards Regression analyses were performed. Next, the Translesion Synthesis E3 ubiquitin ligase, RAD18, was investigated as a potential biomarker in lung cancer. Immunohistochemistry was performed in autopsy samples from an individual donor, and a protocol for subsequent quantitative polymerase chain reaction was created using a control primer set with the experimental samples. The results found that combined mismatch repair gene and oncogene biomarkers were not as powerful as previously described, with other covariates such as biological sex having more predictive power. For RAD18, there did not appear to be a qualitative difference in the amount of RAD18 across tumour samples and normal lung tissue. Overall, further studies with larger sample sizes and quantitative methods will be needed to verify the findings from this study.