Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes

Abstract

Background/aim: Patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) with no progression after induction chemotherapy are usually selected for surgery. Nowadays, response to chemotherapy is not predictable. We aimed to identify genomic predictive markers for response to induction chemotherapy in stage IIIA (N2) NSCLC patients.

Patients and methods: Whole-exome sequencing (WES) was performed on samples from 11 patients with no response after induction chemotherapy and 6 patients with documented pathological response, admitted to the Hotel Dieu Hospital, Paris or Allegemeines Krakenhaus University, Vienna.

Results: A higher alternative allele frequency was found on SENP5, rs63736860, rs1602 and NCBP2, rs553783 in the non-responder group, and on RGP1, rs1570248, SLFN12L, rs2304968, rs9905892, and GBA2, rs3833700 in the responder group.

Conclusion: These polymorphisms contribute to inter-individual sensibility to chemotherapy response. Interrogation of these genetic variations may have potential applicability when deciding the treatment strategy for patients with stage III NSCLC (N2).

Keywords: NSCLC; Whole-exome sequencing; platinum sensitivity.

Figure 1. (A) Study workflow showing number of patients in each group and exclusion reasons. (B) Diagram showing patient distribution in response groups, type of response to treatment and gender (http://sankeymatic.com).

Figure 2. Analysis of SNPs associated with response: (A) Graphical representation of the seven SNPs identified and their location on chromosomes and genes (graph sizes do not take into account real sizes); (B) Forest plot of top 5 five genes altered between Group A (non-responders) and Group B (responders) at p<0.01; (C) Alternative allele frequency of the statistically significant SNPs (p<0.01) between non-responders (Group A) and responders (Group B).

Figure 2. Analysis of SNPs associated with response: (A) Graphical representation of the seven SNPs identified and their location on chromosomes and genes (graph sizes do not take into account real sizes); (B) Forest plot of top 5 five genes altered between Group A (non-responders) and Group B (responders) at p<0.01; (C) Alternative allele frequency of the statistically significant SNPs (p<0.01) between non-responders (Group A) and responders (Group B).

Figure 3. Heatmap matrix of pairwise linkage disequilibrium in 5 European populations for SNPs on chromosome 3 (A); chromosome 9 (B) and chromosome 17 (C) (heatmaps and D’ and R2 were generated using the LDmatrix module from LDlink (6); the shade of red represents the degree of linkage disequilibrium between the pairs.