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

The Pharmacogenomics Journal volume 21, pages 510–519 (2021)Cite this article

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Abstract

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.

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Fig. 1: Normalized gene expression in mucinous versus non-mucinous colorectal cancer. Dashed horizontal line represents median value.
Fig. 2: Kaplan–Meier curves of overall survival in high versus low SRPK1 expression.

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Funding

Funding for this project was provided by the Bons Secours Hospital Dublin through the RCSI StAR MD scholarship and by the Beaumont Hospital Colorectal Research Trust.

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Author notes

  1. These authors contributed equally: J. P. Burke, J. H. M. Prehn

Authors and Affiliations

  1. Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland

    E. O’Connell, I. S. Reynolds, D. A. McNamara & J. P. Burke

  2. Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    E. O’Connell, I. S. Reynolds, M. Salvucci & J. H. M. Prehn

  3. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    D. A. McNamara

  4. Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    J. H. M. Prehn

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O’Connell, E., Reynolds, I.S., Salvucci, M. et al. Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes. Pharmacogenomics J 21, 510–519 (2021). https://doi.org/10.1038/s41397-021-00229-5

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