Genetic polymorphisms of PAI-1 and PAR-1 are associated with acute normal tissue toxicity in Chinese rectal cancer patients treated with pelvic radiotherapy

Abstract

Plasminogen activator inhibitor type 1 (PAI-1) and protease-activated receptor-1 (PAR-1) are crucial mediators of the intestinal microenvironment and are involved in radiation-induced acute and chronic injury. To evaluate whether genetic polymorphisms of PAI-1 and PAR-1 were predictors of radiation-induced injury in patients with rectal cancer, we retrospectively evaluated 356 rectal cancer patients who had received pelvic radiotherapy and analyzed the association of genetic polymorphisms of PAI-1 and PAR-1 with acute toxicities after radiotherapy. Acute adverse events were scored, including dermatitis, fecal incontinence (anal toxicity), hematological toxicity, diarrhea, and vomiting. The patients were grouped into grade ≥2 and grade 0-1 toxicity groups to analyze the acute toxicities. Genotyping of six single nucleotide polymorphisms (SNPs) of PAI-1 and PAR-1 was performed using TaqMan assays. A logistic regression model was used to estimate the odds ratios and 95% confidence intervals. Of the 356 individuals, 264 (72.5%) had grade ≥2 total toxicities; within this group, there were 65 (18.3%) individuals who reached grade ≥3 toxicities. There were 19.5% (69/354) and 36.9% (130/352) patients that developed grade ≥2 toxicities for diarrhea and fecal incontinence, respectively. The variant genotype GG of rs1050955 in PAI-1 was found to be negatively associated with the risk of diarrhea and incontinence (P<0.05), whereas the AG and GG genotypes of rs2227631 in PAI-1 were associated with an increased risk of incontinence. The CT genotype of PAR-1 rs32934 was associated with an increased risk of total toxicity compared with the CC allele. Our results demonstrated that SNPs in the PAI-1 and PAR-1 genes were associated with acute injury in rectal cancer patients treated with pelvic irradiation. These SNPs may be useful biomarkers for predicting acute radiotoxicity in patients with rectal cancer if validated in future studies.

Keywords: acute toxicity; biomarker; pelvic radiotherapy; polymorphism; rectal cancer.

Figure 1

Structural characteristics of the PAI-1 and PAR-1 genes and the results of the LD analysis of the PAI-1 gene. Notes: (A) The PAI-1 gene consists of nine exons, and the three SNPs evaluated in the present study are labeled. (B) The PAR-1 gene consists of two exons, with three SNPs in the area near the 5′ end or 3′UTR labeled. (C) The pairwise LD among five selected SNPs of PAI-1 with potential functional sites. The value within each diamond represents the pairwise correlation between the SNPs (measured as r²). The red indicates high LD values, and the white reflects low values. Abbreviations: UTR, untranslated region; LD, linkage disequilibrium; SNP, single nucleotide polymorphism.