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Original Article | Open Access

Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy

Hongxia Chen1, Luxi Yin1, Jie Yang1, Ningxin Ren1, Jinna Chen1, Qixuan Lu1, Ying Huang1, Yanru Feng2, Weihu Wang2, Shulian Wang2, Yueping Liu2, Yongwen Song2, Yexiong Li2, Jing Jin2 ( ), Wen Tan1 ( ), Dongxin Lin1,3
State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China
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Abstract

Objective

The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment. This study determined the effects of genetic variations in genes involved in apoptosis, pyroptosis, and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy (CRT).

Methods

The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT. The associations between genetic variations and overall survival (OS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs) computed using a Cox proportional regression model. Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase (ALOX5) gene and the ALOX5 rs702365 variant.

Results

We detected 16 genetic polymorphisms in CASP3, CASP7, TRAILR2, GSDME, CASP4, HO-1, ALOX5, GPX4, and NRF2 that were significantly associated with OS in the additive model (P < 0.05). There was a substantial cumulative effect of three genetic polymorphisms (CASP4 rs571407, ALOX5 rs2242332, and HO-1 rs17883419) on OS. Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS. We demonstrated, for the first time, that rs702365 [G] > [C] represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.

Conclusions

Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

Keywords

genetic variationoverall survivalALOX5Rectal neoplasmsregulated cell death

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 20 Issue 4,
April 2023
Pages 297-316
DOI: 10.20892/j.issn.2095-3941.2022.0711
Cite this article:
Chen H, Yin L, Yang J, et al. Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy. Cancer Biology & Medicine, 2023, 20(4): 297-316. https://doi.org/10.20892/j.issn.2095-3941.2022.0711

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Received: 14 December 2022
Accepted: 06 March 2023
Published: 04 May 2023
©2023 Cancer Biology & Medicine.

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