Association of the TYMS 2R/3R Variant (rs45445694) with Chemotherapy Response in Breast Cancer Patients

¹ División de Genética, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, México.
² Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, México.
³ Laboratorio de Inmunofarmacología, Departamento de Farmacología, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Guadalajara, Jalisco, México.
⁴ Departamento de Biología Molecular y Genómica, Instituto de Genética Humana "Dr. Enrique Corona Rivera", Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, México
⁵ División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada 800, Col. Independencia, Guadalajara 44340, Jalisco, México

Academic Editor: Enrico Mini

Published: 23 October 2025 by MDPI in The 1st International Online Conference on Personalized Medicine session Pharmacogenetics, Omics, and Informatics

Abstract:

Introduction

Thymidylate synthase (TYMS) is a key enzyme in DNA synthesis and a primary target of fluoropyrimidine-based chemotherapy. The rs45445694 variant (2R/3R), located in the 5′UTR region of TYMS, may affect gene expression and influence treatment response. This study aimed to evaluate the frequency and clinical relevance of rs45445694 in Mexican breast cancer (BC) patients and its association with chemotherapy response.

Materials and Methods

A total of 785 BC patients were genotyped for the 2R/3R polymorphism and categorized according to chemotherapy response: complete response (n=136), no response (NR, n=311), no response due to recurrence (NRR, n=249), and partial response (PR, n=90). Genotypic frequencies were determined, and associations were evaluated using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results

The 2R/3R genotype was the most frequent across all groups, especially among responders (68%), compared to 57.7% in NR, 62% in NRR, and 58% in PR. The 3R/3R genotype was more prevalent in NR (29.5%) and PR (41%) than in responders (13%). In contrast, the 2R/2R genotype was relatively uncommon, showing similar frequencies in responders (16%) and NR (12.5%), with slightly lower proportions in NRR (11%) and PR (10%). The 3R/3R genotype was significantly associated with increased risk of NR (OR=2.94; 95% CI: 1.67–5.16; p=0.0002), NRR (OR=2.57; p=0.0014), and PR (OR=4.88; p<0.00001). Conversely, the 2R/3R genotype was protective in NR (OR=0.64; p=0.045) and PR (OR=0.45; p=0.005).

Conclusions

The rs45445694 variant of the TYMS gene may influence chemotherapy response in BC. The 3R/3R genotype was associated with poorer outcomes, while 2R/3R appeared more frequently in responders, suggesting a possible protective effect.

Keywords: TYMS; rs45445694; breast cancer; chemotherapy response; pharmacogenetics; genotypes

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