J Cancer 2018; 9(6):1067-1077. doi:10.7150/jca.23538

Research Paper

Genetic variations in the PI3K/PTEN/AKT/mTOR pathway predict tumor response and disease-free survival in locally advanced rectal cancer patients receiving preoperative chemoradiotherapy and radical surgery

Jianhong Peng1*, Wenjuan Ma2*, Zhongguo Zhou3, Yangkui Gu4, Zhenhai Lu1, Rongxin Zhang1✉, Zhizhong Pan1✉

1. Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou, 510060, P.R. China
2. Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou, 510060, P. R. China
3. Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou, 510060, P. R. China;
4. Department of Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou, 510060, P. R. China.
* Jianhong Peng and Wenjuan Ma contributed equally to this work.

Abstract

Objective: Although preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC), the clinical efficacy differs among patients. This study was conducted to determine the association between genetic variations in the PI3K/PTEN/AKT/mTOR pathway and clinical outcomes in LARC patients.

Methods: Sixteen tagging single-nucleotide polymorphisms (SNPs) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) were genotyped. The associations of these SNPs with tumor response to preoperative CRT, postoperative disease-free survival (DFS) and overall survival (OS) were identified. Crude odds ratios (ORs) and hazard ratios (HRs) were adjusted by age, sex, clinical stage, tumor differentiation, tumor location, cycles of preoperative chemotherapy and time interval from CRT completion to surgery.

Results: In an analysis of 97 LARC patients, the G/T+G/G genotype of AKT1:rs2498804 was associated with an increased tumor response rate (adjusted OR = 2.909, 95% confidence interval (CI), 1.127-7.505, P = 0.027). At a median of 65.7 months of follow-up, the G/C+C/C genotype of AKT2:rs8100018 was associated with a reduced risk of postoperative recurrence (adjusted HR = 0.414; 95% CI, 0.187-0.914, P = 0.029). Patients carrying the G/C+C/C genotype in AKT2:rs8100018 presented a higher 5-year DFS rate than those with the wild-type genotype (79.2% vs. 62.3%, P = 0.038). None of the SNPs were significantly associated with pathological complete response (pCR) or 5-year OS.

Conclusions: The current study indicates that genetic variations within the PI3K/ PTEN/AKT/mTOR signaling pathway are associated with the clinical outcomes of LARC patients undergoing preoperative CRT followed by radical surgery.

Keywords: rectal cancer, preoperative chemoradiotherapy, PI3K, clinical outcomes

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How to cite this article:
Peng J, Ma W, Zhou Z, Gu Y, Lu Z, Zhang R, Pan Z. Genetic variations in the PI3K/PTEN/AKT/mTOR pathway predict tumor response and disease-free survival in locally advanced rectal cancer patients receiving preoperative chemoradiotherapy and radical surgery. J Cancer 2018; 9(6):1067-1077. doi:10.7150/jca.23538. Available from http://www.jcancer.org/v09p1067.htm