Abstract
Oxysterols are oxidised derivatives of cholesterol, formed by the enzymatic activity of several cytochrome P450 enzymes and tumour-derived oxysterols have been implicated in tumour growth and survival. The aim of this study was to profile the expression of oxysterol metabolising enzymes in primary colorectal cancer and assess the association between expression and prognosis.Immunohistochemistry was performed on a colorectal cancer tissue microarray containing 650 primary colorectal cancers using monoclonal antibodies to CYP2R1, CYP7B1, CYP8B1, CYP27A1, CYP39A1, CYP46A1 and CYP51A1, which we have developed. Unsupervised hierarchical cluster analysis was used to examine the overall relationship of oxysterol metabolising enzyme expression with outcome and based on this identify an oxysterol metabolising enzyme signature associated with prognosis.Cluster analysis of the whole patient cohort identified a good prognosis group (mean survival=146 months 95% CI 127-165 months) that had a significantly better survival (δ2=12.984, p<0.001, HR=1.983, 95% CI 1.341-2.799) than the poor prognosis group (mean survival=107 months, 95% CI 98-123 months). For the mismatch repair proficient cohort, the good prognosis group had a significantly better survival (δ2=8.985, p=0.003, HR=1.845, 95% CI 1.227-2.774) than the poor prognosis group. Multi-variate analysis showed that cluster group was independently prognostically significant in both the whole patient cohort (p=0.02, HR=1.554, 95% CI 1.072-2.252) and the mismatch repair proficient group (p=0.04, HR=1.530, 95% CI 1.014-2.310).Individual oxysterol metabolising enzymes are overexpressed in colorectal cancer and an oxysterol metabolising enzyme expression profile associated with prognosis has been identified in the whole patient cohort and in mismatch repair proficient colorectal cancers.
Highlights
Colorectal cancer is one of the most common types of malignancy affecting both men and women, with a worldwide annual incidence of greater than 1.2 million new cases [1, 2]
The specificity of the monoclonal antibodies to CYP2R1, CYP7B1, CYP8B1, CYP27A1, CYP39A1, CYP46A1 and CYP51A1 was determined by ELISA using the immunogenic peptides and by immunoblotting using whole cell lysates from cells overexpressing of each protein (Figure 1)
While the molecular pathways involved in the initiation and the early stages of the development of colorectal cancer have been well defined this type of tumour still has a relatively poor prognosis with an overall survival of about 50-60%
Summary
Colorectal cancer is one of the most common types of malignancy affecting both men and women, with a worldwide annual incidence of greater than 1.2 million new cases [1, 2]. The disease remains a leading cause of cancer-related mortality and, despite gradual improvements in prognosis, the 5-year survival remains relatively poor at approximately 55% [1]. Colorectal cancer develops slowly over several years and symptoms often only become apparent in the late stages, many colorectal cancers present at an advanced stage. Patients presenting with distant metastatic disease have a 5-year survival of less than 10% [1]. Colorectal cancer is commonly staged using the tumour, node, metastasis (TNM) staging system to guide treatment decisions and indicate prognosis. Patients with the same stage of tumour often experience a wide range of different clinical outcomes. Despite the unequivocal value of current staging systems, www.impactjournals.com/oncotarget there is a still need to develop reliable biomarkers to more accurately predict prognosis and risk stratify patients with colorectal cancer. Biomarkers can have a variety of roles in colorectal cancer including early detection, predicting prognosis, predicting response to therapy and aiding postoperative monitoring [3]
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