OBJECTIVES: Platinum-based treatment remains the first line chemotherapy for lung cancer. However, some patients cannot tolerate platinum therapy due to acute kidney injury. The purpose of this study is to evaluate the association of genetic polymorphisms with platinum-induced nephrotoxicity in lung cancer patients and build a polygenic risk score to predict high risk patients of platinum induced nephrotoxicity.

METHODS: Twenty-one single nucleotide polymorphisms (SNPs) associated with platinum metabolism were examined in 125 lung cancer patients in Taipei Medical University-Wanfang Medical Center, Taiwan from 2005 to 2011. All clinical and demographic variables were collected from chart review and electronic medical records. Multivariable logistic regression was used to investigate the association between SNPs and platinum induced kidney toxicity. A polygenic risk score adapted from the Framingham study was developed to identify a high risk of kidney toxicity for cisplatin and carboplatin treatment, respectively. C-statistic from receiver operating characteristic (ROC) analysis and Youden’s index were used to assess the model’s predicting performance and a cut-off score to determine high vs low risk, respectively.

RESULTS: Our findings showed 22.4% (N=28) patients had experienced acute kidney injury during platinum-based chemotherapy. The MATE1 G>A (OR_ad= 7.54, p=0.008), OCT2 G808T (OR_ad= 3.44, p=0.029), and OGG1 C326G (OR_ad= 0.243, p=0.043) were associated with platinum induced nephrotoxicity. The C-statistic suggested that our regression model strongly predicted high risk of acute kidney injury for cisplatin (c-statistic=0.819) and carboplatin (c-statistic=0.904) group, respectively. Based on the cut-off score of Youden’s index, high risk patients have higher hazard of developing acute kidney injury than low risk patients in cisplatin (HR= 4.62, p=0.006) and carboplatin treatment (HR= 13.89, p=0.016), respectively.

CONCLUSIONS: Three SNPs associated with platinum induced nephrotoxicity were identified in this study. Our finding suggested that polygenic risk score can help identify lung cancer patients with high risk of kidney toxicity before platinum initiation.