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

Kie Kyon Huang, Kang Won 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, Shenli Zhang, Je Keun Rhee, André L. Vettore, Kakoli Das, Takatsugu Ishimoto, Joo Hang Kim, Yoon Woo Koh, Se Hun KimEun Chang Choi, Bin Tean Teh, Steven G. Rozen, Tae Min Kim, Patrick Tan, Byoung Chul Cho

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    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.

    Original languageEnglish (US)
    Article number19552
    JournalScientific reports
    Volume6
    DOIs
    StatePublished - Jan 21 2016

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    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., ... Cho, B. C. (2016). Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck. Scientific reports, 6, [19552]. https://doi.org/10.1038/srep19552