Genetic variants in PI3K/AKT pathway are associated with severe radiation pneumonitis in lung cancer patients treated with radiation therapy

Yang Tang, Bo Liu, Jing Li, Huanlei Wu, Ju Yang, Xiao Zhou, Mingxiao Yi, Qianxia Li, Shiying Yu, Xianglin Yuan, Yang Tang, Bo Liu, Jing Li, Huanlei Wu, Ju Yang, Xiao Zhou, Mingxiao Yi, Qianxia Li, Shiying Yu, Xianglin Yuan

Abstract

PI3K/AKT pathway plays important roles in inflammatory and fibrotic diseases while its connection to radiation pneumonitis (RP) is unclear. In this study, we explored the associations of genetic variants in PI3K/AKT pathway with RP in lung cancer patients with radiotherapy. Two hundred and sixty one lung cancer patients with radiotherapy were included in this prospective study (NCT02490319) and genotyped by MassArray and Sanger Sequence methods. By multivariate Cox hazard analysis and multiple testing, GA/GG genotype of AKT2: rs33933140 (HR = 0.272, 95% CI: 0.140-0.530, P = 1.3E-4, Pc = 9.1E-4), and the GT/GG genotype of PI3CA: rs9838117 (HR = 0.132, 95% CI: 0.042-0.416, P = 0.001, Pc = 0.006) were found to be strongly associated with a decreased occurrence of RP ≥ grade 3. And patients with the CT/TT genotype of AKT2: rs11880261 had a notably higher incidence of RP ≥ grade 3 (HR = 2.950, 95% CI: 1.380-6.305, P = 0.005, Pc = 0.025). We concluded that the genetic variants of PI3K/AKT pathway were significantly related to RP of grade ≥ 3 and may thus be predictors of severe RP before radiotherapy, if further validated in larger population.

Keywords: AKT; PI3CA; PI3K; SNP; lung cancer; radiation pneumonitis.

© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Patient flow diagram.
Figure 2
Figure 2
Kaplan–Meier estimates RP‐free survival (RP ≥ grade 3) for each genotype. (A) PI3CA: rs9838117; (B) AKT2: rs11880261 (C) AKT2: rs33933140. Patients with GT/GG genotype of PI3CA: rs9838117 (P = 0.0005), the CC genotype of AKT2: rs11880261 (P = 0.006), and the GA/GG genotype of AKT2: rs33933140 (P = 0.0001) had significantly lower risks of RP ≥ grade 3.
Figure 3
Figure 3
Kaplan–Meier estimates effect of genotype in rs33933140 and dosimetric parameters on RP‐free survival (RP ≥ grade 3). (A) rs33933140 and MLD; (B) rs33933140 and V20. Patients with AA genotype of AKT2: rs33933140 and MLD ≥ 15 Gy or V20 ≥ 24% had the highest risk of RP grade ≥ 3 compared with other groups (P < 0.0001 and P < 0.0001, respectively).

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