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

 Kie Kyon Huang  ;  KangWon Jang  ;  Sangwoo Kim  ;  Han Sang Kim  ;  Sung-Moo Kim  ;  Hyeong Ju Kwon  ;  Hye Ryun Kim  ;  Hwan Jung Yun  ;  Myung Ju Ahn  ;  Keon Uk Park  ;  Kalpana Ramnarayanan  ;  John R. McPherson  ;  ShenliZhang  ;  Je-Keun Rhee  ;  André L.Vettore  ;  Kakoli Das  ;  Takatsugu Ishimoto  ;  Joo Hang Kim  ;  Yoon Woo Koh  ;  Se Hun Kim  ;  Eun Chang Choi  ;  Bin Tean Teh  ;  StevenG. Rozen  ;  Tae-Min Kim  ;  Patrick Tan  ;  Byoung Chul Cho 
 SCIENTIFIC REPORTS, Vol.6 : 19552, 2016 
Journal Title
Issue Date
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
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Koh, Yoon Woo(고윤우)
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, Han Sang(김한상) ORCID logo https://orcid.org/0000-0002-6504-9927
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Choi, Eun Chang(최은창)
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