Glutathione‑S‑transferase pi‑1 polymorphisms as predictors of the severity and onset of the development of cumulative oxaliplatin‑induced neurotoxicity in patients with colorectal cancer

Colorectal cancer (CRC) is a major global health burden, and oxaliplatin is a cornerstone of its treatment. However, oxaliplatin‑induced neurotoxicity, particularly chronic cumulative neurotoxicity (CN), poses a significant clinical challenge, often severely compromising the quality of life of patients. Genetic polymorphisms in glutathione S‑transferase pi‑1 (<em>GSTP1</em>) may influence individual susceptibility to oxaliplatin‑induced neurotoxicity. The present study investigated the association between <em>GSTP1</em> polymorphisms (rs1695 and rs1138272) and CN in patients with CRC receiving oxaliplatin‑based chemotherapy. For this purpose, a prospective observational cohort study was conducted across two oncology centers, enrolling 120 patients with CRC. <em>GSTP1</em> polymorphisms were genotyped using polymerase chain reaction and Sanger sequencing. CN severity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events. Logistic regression analysis was used to assess the association between GSTP1 genotypes and neurotoxicity onset and severity. Significant associations were observed between <em>GSTP1</em> polymorphisms and the risk of developing CN. The rs1695 GG genotype conferred a 7.7‑fold increased risk of developing CN at oxaliplatin doses &lt;1,000 mg/m2 (P=0.012) and a 5.5‑fold risk at doses &gt;1,000 mg/m2 (P&lt;0.001). The rs1138272 CT genotype was found to be associated with an elevated risk of developing CN [odds ratio (OR), 4.05; P=0.004], implicating the T allele in susceptibility. The GG genotype was strongly associated with progressive CN severity, exhibiting a 5‑fold risk for grade 2 (P=0.031) and a 6.2‑fold risk for grade 3 CN (P=0.029). Similarly, the CT genotype was associated with grade 3 CN. (OR, 3.43; P=0.043). To the best of our knowledge, the present study is the first to demonstrate a link between the rs1695 and rs1138272 polymorphisms and the onset and severity of CN. On the whole, the present study demonstrates that <em>GSTP1</em> polymorphisms significantly affect the oxaliplatin‑induced risk of developing CN in patients with CRC. These findings advocate genetic screening as part of personalized treatment strategies and underscore the need for further mechanistic and validation studies.