Research Paper|Volume 12, Issue 2|pp 1285—1303

DNAH10 mutation correlates with cisplatin sensitivity and tumor mutation burden in small-cell lung cancer

Man Li¹, Anqi Lin², Peng Luo², Weitao Shen², Dan Xiao¹, Lanying Gou¹, Jian Zhang², Linlang Guo¹

¹Department of Pathology Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People's Republic of China
²Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People's Republic of China

* Equal contribution

Received: October 7, 2019Accepted: December 25, 2019Published: January 20, 2020

Copyright: © 2020 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Chemotherapies based on platinum have been the standard first-line treatment for patients with small-cell lung cancer(SCLC) in the past years. However, the progression of patients occurs mostly due to rapid development of resistance to chemotherapy. In addition, the mechanisms involved in development of cisplatin-resistance in SCLC remain undetermined. Here, we analyzed whole-exome sequencing(WES) datasets from Genomics of Drug Sensitivity in Cancer(GDSC, N=55) and WES data and overall survival(OS) from a published cohort(N=101) to search for cisplatin-resistant target genes and genes associated with poor prognosis. We use our cohort(NCT03162705) as the validation set. We applied single sample gene set enrichment analysis(ssGSEA) to explore the potential molecular mechanisms of cisplatin-resistance. DNAH10 mutations in SCLC was significantly associated with cisplatin-resistance(P=0.0350), poor OS(HR:3.445;P=0.00035) and worse progression-free survival (PFS)(P=0.0142). ssGSEA showed that the negative regulation of FGFR, the SPRY regulation of FGF, and the positive regulation of noncanonical WNT and PI3K/AKT/IKK signaling pathways are differentially up- or downregulated in DNAH10-mutated cell lines. A higher TMB was observed in DNAH10-mutated cell lines. Taken together, DNAH10 mutations may have a potential value in prediction of cisplatin resistance and poor survival in SCLC. Moreover, DNAH10 mutations may have a positive correlation with high TMB in SCLC.