title: Characterisation of the oxysterol metabolising enzyme pathway in mismatch repair proficient and deficient colorectal cancer.
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 (χ2=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 (χ2=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.
authors.affiliation: Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25, 2ZD, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Swan
authors.affiliation: Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25, 2ZD, UK.|Vertebrate Antibodies Ltd, Zoology Department, University of Aberdeen, Aberdeen, AB24 2TZ, UK.
authors.forename: Abdo
authors.initials: A
authors.lastname: Alnabulsi
authors.affiliation: Vertebrate Antibodies Ltd, Zoology Department, University of Aberdeen, Aberdeen, AB24 2TZ, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Cash
authors.affiliation: Vertebrate Antibodies Ltd, Zoology Department, University of Aberdeen, Aberdeen, AB24 2TZ, UK.
authors.forename: Ayham
authors.initials: A
authors.lastname: Alnabulsi
authors.affiliation: Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25, 2ZD, UK.
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Murray
mesh_terms: D000328:Adult; D000368:Aged; D053493:Cholestanetriol 26-Monooxygenase / Q000032:analysis; D000072556:Cholesterol 24-Hydroxylase / Q000032:analysis; D016000:Cluster Analysis; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D000072376:Oxysterols / Q000378:metabolism*; D011379:Prognosis; D013250:Steroid Hydroxylases / Q000032:analysis; D046888:Tissue Array Analysis
chemical_list: D000072376:Oxysterols; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; C499573:CYP39A1 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase
keywords: biomarker; colorectal cancer; cytochrome P450; oxysterol; prognosis