Genetic polymorphisms in 5-Fluorouracil–related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer

Abstract

Background Patients with rectal cancer undergo preoperative neoadjuvant chemoradiation with approximately 70% exhibiting pathologic down-staging in response to treatment. There is currently no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil (5-FU) is regularly used in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase (TS), an enzyme involved in 5-FU metabolism. This may account for observed differences in response to neoadjuvant treatment between patients. Detection of such polymorphisms might identify patients likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid surgery. Methods DNA was isolated from whole blood taken from patients with newly diagnosed rectal cancer who received neoadjuvant therapy (n=50). Response to therapy was calculated with a tumor regression score, based upon histology, from the time of surgery. PCR was performed targeting the promoter region of TS. PCR products were separated using electrophoresis to determine whether patients were homozygous for a double-tandem repeat (2R), a triple-tandem repeat (3R), or heterozygous (2R/3R). A single nucleotide polymorphism (SNP), 3G or 3C, may also be present in the second repeat unit of the 3R allele. Restriction fragment length polymorphism assays were performed in patients with at least one 3R allele using HaeIII. Results Patients with at least one TS 3G allele were more likely to have complete or partial pathological response to 5-FU neoadjuvant therapy (OR 10.4 95% CI 1.3–81.6) (p=0.01) than those without at least one 3G allele. Conclusions Identification of patients with specific genetic polymorphisms in enzymes involved in 5-FU metabolism appears to predict the likelihood of complete or partial pathologic response of rectal cancer to preoperative neoadjuvant therapy.

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…Nikas et al indicated in 108 rectal cancer patients that homozygous C/C genotype in MTHFR gene (rs1801133) were 2.91 times more likely to respond to nCRT ( p = 0.015) and 3.25 times more likely not to have recurrence ( p = 0.008) than either the heterozygous C/T or homozygous T/T genotype [132], which is consistent with previous study [133]. Nelson et al investigated SNP located in the promoter region of the TS gene, which potentially affect the enzymatic activity and catabolism of 5-FU, in 50 rectal cancer patients and found that patients with at least one thymidylate synthase 3G allele were more likely to have a complete or partial pathologic response to nCRT containing 5-FU, with odds ratio of 10.4 (95% CI = 1.3–81.6, p = 0.01), than those without [134]. In addition, xeroderma pigmentosum group G ( XPG ) C46T rs1047768 and mutS homolog 6 ( MSH6 ) rs3136228 have been significantly associated with response to nCRT in rectal cancer [135,136].…”

3′-UTR Polymorphisms in Thymidylate Synthase with Colorectal Cancer Prevalence and Prognosis

“…A number of studies have investigated possible roles for polymorphisms in several 1C metabolism genes in cancer, including those in TS, which may affect CRC susceptibility, disease progression, and TS-targeted chemotherapy [14][15][16][17][18]. Among these are two well-studied TS polymorphisms: (1) TS enhancer region (TSER) 2R/3R and (2) TS 1494del6 [19][20][21].…”