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Title: Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
Authors: Huang, K.K 
Jang, K.W
Kim, S
Kim, H.S
Kim, S.-M
Kwon, H.J
Kim, H.R
Yun, H.J
Ahn, M.J
Park, K.U
Ramnarayanan, K 
McPherson, J.R 
Zhang, S 
Rhee, J.-K
Vettore, A.L 
Das, K 
Ishimoto, T 
Kim, J.H
Koh, Y.W
Kim, S.H
Choi, E.C
Teh, B.T 
Rozen, S.G 
Kim, T.-M
Tan, P 
Cho, B.C
Keywords: cisplatin
DNA binding protein
DNA directed DNA polymerase
quinazolinone derivative
REV3L protein, human
small interfering RNA
Carcinoma, Squamous Cell
dna mutational analysis
drug resistance
gene silencing
Head and Neck Neoplasms
high throughput sequencing
recombination repair
RNA interference
tumor cell line
Carcinoma, Squamous Cell
Cell Line, Tumor
DNA Mutational Analysis
DNA-Binding Proteins
DNA-Directed DNA Polymerase
Drug Resistance, Neoplasm
Gene Silencing
Head and Neck Neoplasms
High-Throughput Nucleotide Sequencing
Recombinational DNA Repair
RNA Interference
RNA, Small Interfering
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Huang, K.K, Jang, K.W, Kim, S, Kim, H.S, Kim, S.-M, Kwon, H.J, Kim, H.R, Yun, H.J, Ahn, M.J, Park, K.U, Ramnarayanan, K, McPherson, J.R, Zhang, S, Rhee, J.-K, Vettore, A.L, Das, K, Ishimoto, T, Kim, J.H, Koh, Y.W, Kim, S.H, Choi, E.C, Teh, B.T, Rozen, S.G, Kim, T.-M, Tan, P, Cho, B.C (2016). Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck. Scientific Reports 6 : 19552. ScholarBank@NUS Repository.
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 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.
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep19552
Appears in Collections:Staff Publications

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