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Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer

The Pharmacogenomics Journal volume 20, pages 524–532 (2020)Cite this article

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Abstract

Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer. A systematic search of PubMed was performed to identify papers investigating drug resistance in colorectal cancer. From this review, a list of 26 drug-resistance-associated genes was compiled. Using patient data from The Cancer Genome Atlas (TCGA), the somatic mutation rate and CNV was compared between patients with mucinous and non-mucinous colorectal cancer. Statistical analysis was carried out using GraphPad PRISM® version 5.00. Data were available on 531 patients (464 non-mucinous, 67 mucinous). A statistically significant difference in the somatic mutation rate between the two cohorts was identified in the TYMP (p = 0.0179), ATP7B (p = 0.0465), SRPK1 (p = 0.0135), ABCB1 (p = 0.0423), and ABCG2 (p = 0.0102) genes. A statistically significant difference in CNV was identified between the two cohorts in the GSTP1 (p = 0.0405), CCS (p = 0.0063), and TOP1 (p = 0.0048) genes. Differences in somatic mutation rate and CNV in genes associated with resistance to 5-FU, oxaliplatin, and irinotecan may partly account for the pattern of resistance observed in mucinous colorectal cancers. These genetic alterations may prove useful when deciding on a personalized approach to chemotherapy and may also represent potential therapeutic targets going forward.

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Funding

Study concept and design—DAM, JPB, JHMP. Study Materials—ISR, EO. Data Collection—ISR, SJF. Data Analysis—ISR, SJF, JPB.

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Author notes

  1. These authors contributed equally: Simon J. Furney, John P. Burke

Authors and Affiliations

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

    Ian S. Reynolds, Emer O’Connell, Deborah A. McNamara & John P. Burke

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

    Ian S. Reynolds, Emer O’Connell, Michael Fichtner, Jochen H. M. Prehn & Simon J. Furney

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

    Deborah A. McNamara

  4. Department of Pathology, Beaumont Hospital, Dublin 9, Ireland

    Elaine W. Kay

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

    Simon J. Furney

  6. Genomic Oncology Research Group, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    Simon J. Furney

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  1. Ian S. Reynolds
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  2. Emer O’Connell
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  7. Simon J. Furney
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Contributions

Funding for this project was provided by the Beaumont Hospital Colorectal Research Fund & Science Foundation Ireland (15/ERACSM/3268).

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Correspondence to Simon J. Furney or John P. Burke.

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Reynolds, I.S., O’Connell, E., Fichtner, M. et al. Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer. Pharmacogenomics J 20, 524–532 (2020). https://doi.org/10.1038/s41397-019-0137-6

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