Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck

Sci Rep. 2016 Jan 21:6:19552. doi: 10.1038/srep19552.

Abstract

Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA. Platinum-based chemotherapy elevated the mutation rates of SCCHN compared to chemotherapy-naïve SCCHNs. Cisplatin-treated SCCHN genomes uniquely exhibited a novel mutational signature characterized by C:G to A:T transversions at CCR sequence contexts that may have arisen due to error-prone translesional synthesis. Somatic mutations in REV3L, the gene encoding the catalytic subunit of DNA polymerase ζ involved in translesional synthesis, are significantly enriched in a subset of patients who derived extended clinical benefit to dacomitinib (P = 0.04). Functional assays showed that loss-of-function of REV3L dramatically enhanced the sensitivity of SCCHN cells to dacomitinib by the loss of both translesion synthesis and homologous recombination pathways. Our data suggest that the 'platinum' mutational signature and inactivation of REV3L may inform treatment options in patients of recurrent SCCHN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • DNA-Directed DNA Polymerase / genetics*
  • Drug Resistance, Neoplasm / genetics*
  • Exome*
  • Gene Silencing
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics*
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Mutation*
  • Quinazolinones / pharmacology
  • Quinazolinones / therapeutic use
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Recombinational DNA Repair
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • DNA-Binding Proteins
  • Quinazolinones
  • RNA, Small Interfering
  • dacomitinib
  • DNA-Directed DNA Polymerase
  • REV3L protein, human
  • Cisplatin