Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer

The Pharmacogenomics Journal volume 21, pages 285–295 (2021)Cite this article

Subjects

Abstract

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49–0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44–0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19–0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Progression-free survival (PFS) in the validation cohort: MS4A12 rs4939378 variants.
Fig. 2: Progression-free survival (PFS) in the control cohort: MS4A12 rs4939378 variants.

Similar content being viewed by others

References

  1. Song N, Pogue-Geile KL, Gavin PG, Yothers G, Kim SR, Johnson NL, et al. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial. JAMA Oncol. 2016;2:1162–9.

    Article  Google Scholar 

  2. Snoeck V, Goddeeris B, Cox E. The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect. 2005;7:997–1004.

    Article  CAS  Google Scholar 

  3. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619–25.

    Article  CAS  Google Scholar 

  4. Koslowski M, Sahin U, Dhaene K, Huber C, Türeci O. MS4A12 is a colon-selective store-operated calcium channel promoting malignant cell processes. Cancer Res. 2008;68:3458–66.

    Article  CAS  Google Scholar 

  5. Koslowski M, Türeci O, Huber C, Sahin U. Selective activation of tumor growth-promoting Ca2+ channel MS4A12 in colon cancer by caudal type homeobox transcription factor CDX2. Mol Cancer. 2009;8:77.

    Article  Google Scholar 

  6. Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med. 2016;374:211–22.

    Article  CAS  Google Scholar 

  7. He L, Deng HY, Wang C, Decreased X. expression of MS4A12 inhibits differentiation and predicts early stage survival in colon cancer. Neoplasma. 2017;64:65–73.

    Article  CAS  Google Scholar 

  8. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371:1609–18.

    Article  Google Scholar 

  9. Suenaga M, Mizunuma N, Matsusaka S, Shinozaki E, Ueno M, Yamaguchi T. Retrospective analysis on the efficacy of bevacizumab with FOLFOX as a first-line treatment in Japanese patients with metastatic colorectal cancer. Asia Pac J Clin Oncol. 2014;10:322–9.

    Article  Google Scholar 

  10. Lee PH, Shatkay H. F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic Acids Res. 2008;36:D820–4. Database issue

    Article  CAS  Google Scholar 

  11. Kim SR, Song N, Yothers G, Gavin PG, Allegra CJ, Paik S, et al. Tumour sidedness and intrinsic subtypes in patients with stage II/III colon cancer: analysis of NSABP C-07 (NRG Oncology). Br J Cancer. 2018;118:629–633.

    Article  Google Scholar 

  12. Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA, et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol. 2011;29:1120–7.

    Article  CAS  Google Scholar 

  13. Drew JE, Farquharson AJ, Mayer CD, Vase HF, Coates PJ, Steele RJ, et al. Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma. PLoS ONE. 2014;9:e113071.

    Article  Google Scholar 

  14. Ren D, Zheng G, Bream S, Tevebaugh W, Shaheen NJ, Chen X. Single nucleotide polymorphisms of caudal type homeobox 1 and 2 are associated with Barrett’s esophagus. Dig Dis Sci. 2014;59:57–63.

    Article  CAS  Google Scholar 

  15. Findlay JM, Middleton MR, Tomlinson I. Genetic biomarkers of Barrett’s esophagus susceptibility and progression to dysplasia and cancer: a systematic review and meta-analysis. Dig Dis Sci. 2016;61:25–38.

    Article  CAS  Google Scholar 

  16. Bae JM, Lee TH, Cho NY, Kim TY, Kang GH. Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol. 2015;21:1457–67.

    Article  CAS  Google Scholar 

  17. Aasebø K, Dragomir A, Sundström M, Mezheyeuski A, Edqvist PH, Eide GE, et al. CDX2: a prognostic marker in metastatic colorectal cancer defining a better BRAF mutated and a worse KRAS mutated subgroup. Front Oncol. 2020;10:8.

    Article  Google Scholar 

  18. Orlandi A, Di Salvatore M, Bagalà C, Basso M, Strippoli A, Plastino F, et al. ERCC1 induction after oxaliplatin exposure may depend on KRAS mutational status in colorectal cancer cell line: in vitro veritas. J Cancer. 2015;6:70–81.

    Article  CAS  Google Scholar 

  19. Maddukuri L, Dudzińska D, Tudek B. Bacterial DNA repair genes and their eukaryotic homologues: 4. The role of nucleotide excision DNA repair (NER) system in mammalian cells. Acta Biochim Pol. 2007;54:469–82.

    Article  CAS  Google Scholar 

  20. Kokoska ER, Wolff AB, Smith GS, Miller TA. Epidermal growth factor-induced cytoprotection in human intestinal cells involves intracellular calcium signaling. J Surg Res. 2000;88:97–103.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was partly supported by the National Cancer Institute (grant number P30CA014089), The Gloria Borges WunderGlo Foundation—The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund and Call to Cure Fund. Mitsukuni Suenaga is the recipient of Takashi Tsuruo Memorial Fund. Martin D. Berger received a grant from the Swiss Cancer League (BIL KLS-3334-02-2014) and the Werner and Hedy Berger-Janser Foundation for cancer research. YM received a grant from Japan Society for the Promotion of Science (S2606). We thank Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA

    Mitsukuni Suenaga, Marta Schirripa, Wu Zhang, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Shivani Soni, Afsaneh Barzi & Heinz-Josef Lenz

  2. Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Mitsukuni Suenaga & Toshiharu Yamaguchi

  3. Department of Specialized Surgeries, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Mitsukuni Suenaga

  4. Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), via Gattamelata 64, 35128, Padua, Italy

    Marta Schirripa, Sara Lonardi & Fotios Loupakis

  5. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA

    Shu Cao

  6. Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126, Pisa, Italy

    Chiara Cremolini & Alfredo Falcone

Authors
  1. Mitsukuni Suenaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Schirripa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chiara Cremolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Lonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoshi Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin D. Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuji Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shivani Soni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Afsaneh Barzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Toshiharu Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Fotios Loupakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alfredo Falcone
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Heinz-Josef Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitsukuni Suenaga.

Ethics declarations

Conflict of interest

All authors have read the journal’s policy on disclosure of potential conflicts of interest. CC is a consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono, Servier. AF is a consultant/advisory board member for Bayer, Roche, Amgen, Eli-Lilly, Merck Serono, Bristol-Myers Squibb, Sanofi, and Servier. H-JL is consultant /advisory board member for Bristol-Myers Squibb, Merck Serono, and Bayer. All remaining authors have no conflicts of interest to declare in this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suenaga, M., Schirripa, M., Cao, S. et al. Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer. Pharmacogenomics J 21, 285–295 (2021). https://doi.org/10.1038/s41397-021-00207-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-021-00207-x

Search

Advanced search

Quick links