Multi-loci analysis reveals the importance of genetic variations in sensitivity of platinum-based chemotherapy in non-small-cell lung cancer

Abstract

Polymorphisms in DNA repair and apoptotic pathways may cause variations in chemosensitivity of non-small-cell lung cancer (NSCLC) through complex gene-gene and gene-environment interactions. A total of 200 advanced NSCLC patients who received platinum-based chemotherapies were recruited. The short-term clinical outcomes were classified as chemosensitive group, including complete remission (CR) and partial remission (PR), and chemoresistant group, namely stable disease (SD) and progression disease (PD) at the end of treatment. We applied multifactor dimensionality reduction (MDR), classification and regression tree (CART) and traditional logistic regression (LR) to explore high-order gene-gene and gene-environment interactions among 11 functional single nucleotide polymorphisms (SNPs), smoking status, cancer stages and treatment regimens in the response to chemotherapy. Multi-loci analyses consistently indicated that interactions among XRCC1 Arg194Trp, XPC PAT, FAS G-1377A, and FASL T-844C were associated with sensitivity to platinum-based chemotherapy. In MDR analysis, the four-factor model yielded the highest test accuracy of 0.72 (permutation P = 0.001). In CART analysis, these four SNPs were the determinant nodes of the growth of regression tree. Patients carrying XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed completely no response to platinum, whereas patients with XRCC1 194Trp allele and XPC PAT +/+ had 68.8% response rate to platinum. In LR analysis, a significant gene-dosage effect was detected along with the increasing number of favorable genotypes of these four polymorphisms (P trend = 0.00002). Multi-loci analysis reveals the importance of genetic variations involved in DNA repair and apoptotic pathways in sensitivity of platinum-based chemotherapy in NSCLC.

Keywords: classification and regression tree; multifactor dimensionality reduction; single nucleotide polymorphism.