title: Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kie Kyon
authors.initials: KK
authors.lastname: Huang
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Kang Won
authors.initials: KW
authors.lastname: Jang
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea.|Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
authors.forename: Han Sang
authors.initials: HS
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyeong Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Hematology-Oncology, Chungnam National University, Daejeon, Korea.
authors.forename: Hwan Jung
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Myung Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Hematology-Oncology, Keimyung University, Daegu, Korea.
authors.forename: Keon Uk
authors.initials: KU
authors.lastname: Park
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ramnarayanan
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.|Duke-NUS Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: John R
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Shenli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Je-Keun
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: André L
authors.initials: AL
authors.lastname: Vettore
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kakoli
authors.initials: K
authors.lastname: Das
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yoon Woo
authors.initials: YW
authors.lastname: Koh
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Se Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Chang
authors.initials: EC
authors.lastname: Choi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.|Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.|Duke-NUS Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.|Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D059767:Recombinational DNA Repair; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D004268:DNA-Binding Proteins; D052999:Quinazolinones; D034741:RNA, Small Interfering; C525726:dacomitinib; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; D002945:Cisplatin