Abstract 3949: Whole exome sequencing of platinum-refractory recurrent or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) reveals a novel cisplatin mutational signature and REV3L mutation as a molecular predictor for dacomitinib, a p
Authors: Cho Byoung Chul , Kim Han Sang , Ahn Myung-Ju , Park Keon Uk , Lee Se-Hoon , Yun Hwan Jung , Kyon Huang Kie , Kim Tae-Min , Tan Patrick 
Published: August 2015

Abstract
REV3L, a catalytic subunit of DNA polymerase zeta, is essential for tolerance of DNA damage via error-prone translesion synthesis. The goals of this study were to investigate the mutational landscape and predictive biomarkers of dacomitinib, Pan-ErbB inhibitor, in platinum-pretreated R/M-SCCHN.
Nineteen patients with R/M-SCCHN, who were refractory to platinum-based chemotherapy (18) or considered platinum-intolerant (1), were treated with dacomitinib 45mg/day. For fresh tumor samples taken immediately before treatment, whole exome-sequencing was performed. MuTect and SomaticIndelDetector were used to identify somatic SNVs and indels. For mutation signature analysis, we calculated the frequency of coding SNVs according to the 3 letter-based 96 trinucleotide classification system. Mutational profiles identified were compared with 306 treatment-naïve SCCHN samples from TCGA. MutSig algorithm was used to identify the recurrent mutations.
Tumor genomes were sequenced to a median coverage of 149X and matched normal blood genomes were sequenced as 150bp paired-ends to a coverage of 89X. Overall, we identified 10,289 somatic SNVs and Indels. Compared with 306 TCGA SCCHN, platinum-refractory SCCHN genomes showed higher mutations rates (median 13.2 vs. 5.3 mutations per Mb; P &lt;0.001) and lower Ti/Tv ratios (0.79 vs. 1.27), which were largely attributed to the overrepresentation of C&gt;A transversions. We extracted five distinct mutational signatures each of which represents unique mutational processes operative SCCHN genomes. In addition to the four signatures that have been previously reported in SCCHN (APOBEC, age, ultraviolets, smoking), we identified a novel mutational signature that has not been previously reported. This novel signature is characterized by the prominence of C&gt;A mutations mainly occurring on CpCpA and CpCpG trinucleotide contexts, which is closely associated with the action mechanism of cisplatin. Among 33 recurrent mutations, only REV3L mutation showed significant enrichment in responders (P = 0.0316). Of note, the frequency of REV3L mutations was higher in our data compared with that in TCGA data (21% vs. 3.9%; P = 0.0493), which was supported by the fact that REV3L mutations were not found in pre-cisplatin tumor samples in the same patients. In various in vitro assays, REV3L depletion synergized with dacomitinib to inhibit SCCHN cell growth by arresting cell cycle and inhibiting homologous recombinational repair.
In the whole exome sequencing of cisplatin-refractory SCCHN, we found a novel cisplatin mutational signature, which has not been found in treatment-naïve tumors and therefore may have therapeutic implications. REV3L mutation is a novel molecular predictor for the better efficacy of dacomitinib.
Citation Format: Byoung Chul Cho, Han Sang Kim, Myung-Ju Ahn, Keon Uk Park, Se-Hoon Lee, Hwan Jung Yun, Huang Kie Kyon, Tae-Min Kim, Patrick Tan. Whole exome sequencing of platinum-refractory recurrent or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) reveals a novel cisplatin mutational signature and REV3L mutation as a molecular predictor for dacomitinib, a p [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3949. doi:10.1158/1538-7445.AM2015-3949