Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer
- 4 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The Pharmacogenomics Journal
- Vol. 21 (3), 285-295
- https://doi.org/10.1038/s41397-021-00207-x
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA014089)
This publication has 20 references indexed in Scilit:
- Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal CancerThe New England Journal of Medicine, 2014
- Single Nucleotide Polymorphisms of Caudal Type Homeobox 1 and 2 Are Associated with Barrett’s EsophagusDigestive Diseases and Sciences, 2013
- Retrospective analysis on the efficacy of bevacizumab with FOLFOX as a first-line treatment in Japanese patients with metastatic colorectal cancerAsia-Pacific Journal of Clinical Oncology, 2013
- A colorectal cancer classification system that associates cellular phenotype and responses to therapyNature Medicine, 2013
- Single-cell dissection of transcriptional heterogeneity in human colon tumorsNature Biotechnology, 2011
- Selective activation of tumor growth-promoting Ca2+ channel MS4A12 in colon cancer by caudal type homeobox transcription factor CDX2Molecular Cancer, 2009
- MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell ProcessesCancer Research, 2008
- F-SNP: computationally predicted functional SNPs for disease association studiesNucleic Acids Research, 2007
- The role of enterocytes in the intestinal barrier function and antigen uptakeMicrobes and Infection, 2005
- Epidermal Growth Factor-Induced Cytoprotection in Human Intestinal Cells Involves Intracellular Calcium SignalingJournal of Surgical Research, 2000