Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes

• Published in: The pharmacogenomics journal Vol. 21; no. 4; pp. 510 - 519
• Main Authors: O’Connell, E., Reynolds, I. S., Salvucci, M., McNamara, D. A., Burke, J. P., Prehn, J. H. M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group
• Subjects: 38/91; 631/67/69; 692/53/2423; Aged; Biomedical and Life Sciences; Biomedicine; Cancer; Chemoresistance; Chemotherapy; Colorectal cancer; Colorectal Neoplasms - genetics; Copper-Transporting ATPases - genetics; Drug metabolism; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Female; Gene Expression; Gene Expression - genetics; Gene frequency; Genetic aspects; Genomes; Human Genetics; Humans; Inactivation, Metabolic - genetics; Male; Metastases; Multivariate analysis; Oncology; Oncology, Experimental; Oxaliplatin; Patient outcomes; Pharmacotherapy; Prognosis; Protein Serine-Threonine Kinases - genetics; Psychopharmacology; Rectum; Survival; Ireland
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/s41397-021-00229-5

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan–Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS , TYMP , and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC ( p  < 0.001, p  = 0.003, p  < 0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC ( p  = 0.004, p  = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p  < 0.001), node positive disease (OR = 0.49, p  = 0.005), and metastatic disease (OR = 0.32, p  < 0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p  = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression ( p  = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.