Nucleotide excision repair and response and survival to chemotherapy in colorectal cancer patients

Abstract Background: XPF is a key factor contributing to DNA damage excision of nucleotide excision repair pathway. The relationship between XPF expression and the risk and prognosis of colorectal cancer (CRC) is unclear. Methods: In this experiment, a total of 824 cases of colorectal tissue were collected. XPF protein expression was detected by immunohistochemical staining. In order to explore the differential expression of XPF between CRC and non-cancer controls, and the correlation between XPF expression and CRC clinicopathological parameters, we conducted a non-parametric test. Univariate and multivariate Cox regression analyses were conducted to investigate the relationship between XPF expression and CRC prognosis. The Java based software GSEA as well as STRING, David, GO, KEGG were used to explore the function and regulation network of XPF. Results: The results demonstrated that the XPF expression in CRC was significantly up-regulated compared with non-tumor controls (P < 0.001) and adenoma tissues (P < 0.001). XPF protein was highly expressed in the dynamic sequence of anal diseases to adenoma tissues to CRC. Expression of XPF was related to tumor location (P=0.005) and with tumor growth pattern (P=0.009). The results of prognosis analysis suggested that in individuals with T1-2 invasive extent, XPF low expression may be significantly associated with better overall survival (HR = 7.978, 95% CI: 1.208-52.673, P = 0.031). XPF and its interacting genes played a vital role in different processes of nucleotide excision repair pathway. XPF expression was related with Ubiquitin like protein specific protease activity.Conclusions: XPF might be a promising biomarker for CRC risk, and also showed potential as a prognostic predictor in CRC patients.

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Evaluation of thymidylate synthase and ERCC1 mRNA levels as predictive markers in colorectal cancer patients treated with S-1 and oxaliplatin

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15071 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15071-e15071

Author(s):

H. Kuramochi ◽

K. Hayashi ◽

G. Nakajima ◽

H. Kamikozuru ◽

M. Yamamoto

Keyword(s):

Colorectal Cancer ◽

Mrna Expression ◽

Real Time ◽

Cancer Patients ◽

Thymidylate Synthase ◽

Excision Repair ◽

Mrna Levels ◽

Expression Levels ◽

Colorectal Cancer Patients ◽

Mrna Expression Levels

e15071 Background: Oxaliplatin has been widely used for the treatment of colorectal cancer. The mechanism of action of platinum compounds such as oxaliplatin is to bind to a DNA molecule in the form of a platinum-DNA-adduct. Excision repair cross complementation group 1 (ERCC1), which plays a major role in the nucleotide excision pathway, has a polymorphism in codon 118, and is reported to be associated with a resistance to platinum-based therapy. Thymidylate synthase (TS) and dehydropyrimidine dehydrogenase (DPD) are key enzymes of 5-FU metabolism and are well known to be associated with a response to 5-FU-based therapy. Methods: Twenty-one colorectal cancer patients (male:female = 7:14; median age, 65) treated with a combination of oxaliplatin and S-1 as a first-line therapy were analyzed for ERCC1 codon 118 polymorphism and the mRNA expression levels of TS, ERCC1, and DPD. Formalin-fixed paraffin- embedded surgical specimens were used and t-RNA and DNA were extracted. The mRNA expression levels were measured using real-time RT-PCR, and the polymorphism was analyzed using the allelic discrimination method together with real-time PCR. Results: No correlation was observed between ERCC1 codon118 polymorphism and any response to the chemotherapy. ERCC1 mRNA levels tended to be higher in the patients with wild-type homozygous alleles in codon 118 than in those with at least one mutant allele(1.19 vs.0.68: p= 0.15). Patients with both high TS and ERCC1 mRNA levels showed a significantly lower response rate than the others (25% vs. 67%, p=0.02). No relationship was seen between DPD mRNA expression levels and the response. Conclusions: The mRNA expression levels of TS and ERCC1 appear to be useful markers for the treatment of S-1 and oxaliplatin. No particular usefulness of ERCC1 codon 118 polymorphism was verified. No significant financial relationships to disclose.

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