Pharmacogenomics of Colorectal Cancer Treatment

Pharmacogenomics integrates genetic and genomic data to tailor colorectal cancer therapies according to individual molecular profiles. Standard regimens such as FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) are subject to marked interindividual variability in efficacy and toxicity. Key determinants include germline variants in DPYD influencing fluoropyrimidine metabolism, UGT1A1 polymorphisms affecting irinotecan clearance, and somatic mutations in RAS–RAF–MAPK pathway genes that confer resistance to anti-EGFR monoclonal antibodies. In addition, alterations in one-carbon metabolism gene expression (for instance MTHFR and TYMS) and DNA repair genes (such as ERCC1 and XRCC1) modulate response to oxaliplatin and fluoropyrimidines. Emerging proteomic and transcriptomic approaches promise more refined biomarker panels, broadening the scope of personalised treatment in metastatic and adjuvant settings. Such advances carry global significance by optimising therapeutic indices, reducing adverse effects and guiding novel targeted therapies.

Research from Nature Portfolio

Recent studies have applied targeted multiplex proteomics to metastatic colorectal cancer samples, enabling simultaneous quantification of over fifty proteins implicated in oncogenesis, drug metabolism and resistance. This approach uncovered differential expression of EGFR, KRAS, topoisomerases and mesothelin according to RAS mutation status, and identified loss of PTEN protein as a predictor of reduced progression-free survival on anti-EGFR therapies. Crucially, proteomic profiling revealed potential actionable targets in a majority of tumours without genomic aberrations, demonstrating that protein-level analyses can complement genomic testing to refine patient stratification and trial eligibility.

Pharmacogenomics of Colorectal Cancer Treatment publication trend

The graph below shows the total number of articles in pharmacogenomics of colorectal cancer treatment across all publications each year (not limited to Nature Index journals).

Technical terms

Pharmacogenomics: Study of how genetic variation affects drug response.

Single nucleotide polymorphism (SNP): A single base change in the genome that may alter gene function.

5-Fluorouracil (5-FU): A pyrimidine analogue used as a chemotherapy agent.

DPYD: Gene encoding dihydropyrimidine dehydrogenase, the principal enzyme in 5-FU catabolism.

UGT1A1: Enzyme responsible for glucuronidation of irinotecan’s active metabolite.

RAS–RAF pathway: Signalling cascade frequently mutated in colorectal cancer, modulating response to anti-EGFR therapy.

Proteomics: Large-scale study of proteins to assess expression and modifications in disease contexts.

References

1. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer. Scientific Reports (2019).
2. Colon Cancer Pharmacogenetics: A Narrative Review. Pharmacy (2022).
3. Pathway analysis of genetic variants in folate‐mediated one‐carbon metabolism‐related genes and survival in a prospectively followed cohort of colorectal cancer patients. Cancer Medicine (2018).
4. Association of DNA repair gene variants with colorectal cancer: risk, toxicity, and survival. BMC Cancer (2020).