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

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 genet...

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Main Authors:	Huang, Kie Kyon, Jang, Kang Won, Kim, Sangwoo, Kim, Han Sang, Kim, Sung-Moo, Kwon, Hyeong Ju, Kim, Hye Ryun, Yun, Hwan Jung, Ahn, Myung Ju, Park, Keon Uk, Ramnarayanan, Kalpana, McPherson, John R., Zhang, Shenli, Rhee, Je-Keun, Vettore, André L., Das, Kakoli, Ishimoto, Takatsugu, Kim, Joo Hang, Koh, Yoon Woo, Kim, Se Hun, Choi, Eun Chang, Teh, Bin Tean, Rozen, Steven G., Kim, Tae-Min, Tan, Patrick, Cho, Byoung Chul
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726344/

id	pubmed-4726344
recordtype	oai_dc
spelling	pubmed-47263442016-01-27 Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck Huang, Kie Kyon Jang, Kang Won Kim, Sangwoo Kim, Han Sang Kim, Sung-Moo Kwon, Hyeong Ju Kim, Hye Ryun Yun, Hwan Jung Ahn, Myung Ju Park, Keon Uk Ramnarayanan, Kalpana McPherson, John R. Zhang, Shenli Rhee, Je-Keun Vettore, André L. Das, Kakoli Ishimoto, Takatsugu Kim, Joo Hang Koh, Yoon Woo Kim, Se Hun Choi, Eun Chang Teh, Bin Tean Rozen, Steven G. Kim, Tae-Min Tan, Patrick Cho, Byoung Chul Article 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. Nature Publishing Group 2016-01-21 /pmc/articles/PMC4726344/ /pubmed/26790612 http://dx.doi.org/10.1038/srep19552 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huang, Kie Kyon Jang, Kang Won Kim, Sangwoo Kim, Han Sang Kim, Sung-Moo Kwon, Hyeong Ju Kim, Hye Ryun Yun, Hwan Jung Ahn, Myung Ju Park, Keon Uk Ramnarayanan, Kalpana McPherson, John R. Zhang, Shenli Rhee, Je-Keun Vettore, André L. Das, Kakoli Ishimoto, Takatsugu Kim, Joo Hang Koh, Yoon Woo Kim, Se Hun Choi, Eun Chang Teh, Bin Tean Rozen, Steven G. Kim, Tae-Min Tan, Patrick Cho, Byoung Chul
spellingShingle	Huang, Kie Kyon Jang, Kang Won Kim, Sangwoo Kim, Han Sang Kim, Sung-Moo Kwon, Hyeong Ju Kim, Hye Ryun Yun, Hwan Jung Ahn, Myung Ju Park, Keon Uk Ramnarayanan, Kalpana McPherson, John R. Zhang, Shenli Rhee, Je-Keun Vettore, André L. Das, Kakoli Ishimoto, Takatsugu Kim, Joo Hang Koh, Yoon Woo Kim, Se Hun Choi, Eun Chang Teh, Bin Tean Rozen, Steven G. Kim, Tae-Min Tan, Patrick Cho, Byoung Chul Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
author_facet	Huang, Kie Kyon Jang, Kang Won Kim, Sangwoo Kim, Han Sang Kim, Sung-Moo Kwon, Hyeong Ju Kim, Hye Ryun Yun, Hwan Jung Ahn, Myung Ju Park, Keon Uk Ramnarayanan, Kalpana McPherson, John R. Zhang, Shenli Rhee, Je-Keun Vettore, André L. Das, Kakoli Ishimoto, Takatsugu Kim, Joo Hang Koh, Yoon Woo Kim, Se Hun Choi, Eun Chang Teh, Bin Tean Rozen, Steven G. Kim, Tae-Min Tan, Patrick Cho, Byoung Chul
author_sort	Huang, Kie Kyon
title	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
title_short	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
title_full	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
title_fullStr	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
title_full_unstemmed	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck
title_sort	exome sequencing reveals recurrent rev3l mutations in cisplatin-resistant squamous cell carcinoma of head and neck
description	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.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726344/
_version_	1613528222724521984

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

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