Thymidylate synthase locus LOH in combination with genotype has prognostic and predictive significance in colorectal cancer

Kotake,Masanori; Bando,Hiroyuki; Kaneko,Mami; Takemura,Hirofumi; Minamoto,Toshinari; Kawakami,Kazuyuki

doi:10.3892/mco.2021.2398

Thymidylate synthase locus LOH in combination with genotype has prognostic and predictive significance in colorectal cancer

Authors:
- Masanori Kotake
- Hiroyuki Bando
- Mami Kaneko
- Hirofumi Takemura
- Toshinari Minamoto
- Kazuyuki Kawakami
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Affiliations: Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan, Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa 920‑8530, Japan, Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920‑0934, Japan
Published online on: September 17, 2021 https://doi.org/10.3892/mco.2021.2398
Article Number: 235
Copyright: © Kotake et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the current study was to investigate the prognostic and predictive significance of polymorphisms in the thymidylate synthase (TS) gene, alongside the loss of heterozygocity (LOH) at this gene locus in patients with colorectal cancer. Genotyping was carried out for a variable number tandem repeat (VNTR) polymorphism in the TS 5'‑untranslated region, a G/C single nucleotide polymorphism (SNP) located within this VNTR, and for TS LOH status in 246 colorectal cancer and paired normal DNA samples. The results were analyzed in relation to clinicopathological features, including the prognostic and predictive significance of TS genotype in patients who underwent curative surgery. Complete VNTR, SNP and LOH information for TS was obtained in 226 cases. No significant associations were observed between normal tissue TS genotype status and clinicopathological features. LOH of TS was observed in 58% of tumor samples and was associated with poor prognosis independently of clinical stage. Cases exhibiting TS LOH were classified into the three groups of 2R/loss, 3G/loss and 3C/loss. Patients with 3C/loss genotype status had poor outcomes when treated by surgery alone, but their survival was similar to patients with other genotypes following Fluorouracil (5‑FU)‑based adjuvant chemotherapy. The results suggested that LOH of the TS locus may be a significant prognostic factor in colorectal cancer, with the genotype of the residual allele also demonstrating an influence on prognosis. In conclusion, LOH status should be considered when TS genotype is explored as a potential prognostic and predictive marker for 5‑FU‑based adjuvant chemotherapy in colorectal cancer.

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