Colorectal cancer is one of the most common types of
cancer with over fifty percent of patients presenting at an advanced stage.
Retinoic acid is a metabolite of
vitamin A and is essential for normal cell growth and aberrant
retinoic acid metabolism is implicated in tumourigenesis. This study has profiled the expression of
retinoic acid metabolising
enzymes using a well characterised
colorectal cancer tissue microarray containing 650 primary
colorectal cancers, 285
lymph node metastasis and 50 normal colonic mucosal samples. Immunohistochemistry was performed on the tissue microarray using
monoclonal antibodies which we have developed to the
retinoic acid metabolising
enzymes CYP26A1,
CYP26B1, CYP26C1 and
lecithin retinol acyl
transferase (LRAT) using a semi-quantitative scoring scheme to assess expression. Moderate or strong expression of CYP26A1was observed in 32.5% of
cancers compared to 10% of normal colonic epithelium samples (p<0.001).
CYP26B1 was moderately or strongly expressed in 25.2% of tumours and was significantly less expressed in normal colonic epithelium (p<0.001). CYP26C1 was not expressed in any sample. LRAT also showed significantly increased expression in primary
colorectal cancers compared with normal colonic epithelium (p<0.001). Strong
CYP26B1 expression was significantly associated with poor prognosis (HR = 1.239, 95%CI = 1.104-1.390, χ(2) = 15.063, p = 0.002). Strong LRAT was also associated with poorer outcome (HR = 1.321, 95%CI = 1.034-1.688, χ(2) = 5.039, p = 0.025). In mismatch repair proficient tumours strong
CYP26B1 (HR = 1.330, 95%CI = 1.173-1.509, χ(2)= 21.493, p<0.001) and strong LRAT (HR = 1.464, 95%CI = 1.110-1.930, χ(2) = 7.425, p = 0.006) were also associated with poorer prognosis. This study has shown that the
retinoic acid metabolising
enzymes CYP26A1,
CYP26B1 and LRAT are significantly overexpressed in
colorectal cancer and that
CYP26B1 and LRAT are significantly associated with prognosis both in the total cohort and in those tumours which are mismatch repair proficient.
CYP26B1 was independently prognostic in a multivariate model both in the whole patient cohort (HR = 1.177, 95%CI = 1.020-1.216, p = 0.026) and in mismatch repair proficient tumours (HR = 1.255, 95%CI = 1.073-1.467, p = 0.004).