Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck.
作者： Kie Kyon Huang , Kang Won Jang , Sangwoo Kim , Han Sang Kim , Sung-Moo Kim
DOI: 10.1038/SREP19552
关键词:
摘要: 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 benefit from this therapeutic option. To characterize the genetic landscape cisplatin-treated SCCHN genomes potential for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic tumors their matched germline DNA. Platinum-based chemotherapy elevated mutation rates compared chemotherapy-naive SCCHNs. Cisplatin-treated uniquely exhibited a novel mutational signature characterized by C:G A:T transversions at CCR sequence contexts that may have arisen due error-prone translesional synthesis. Somatic mutations REV3L, gene encoding catalytic subunit DNA polymerase ζ involved synthesis, significantly enriched subset who derived extended (P = 0.04). Functional assays showed loss-of-function REV3L dramatically enhanced sensitivity cells loss both translesion synthesis homologous recombination pathways. Our data suggest 'platinum' inactivation inform treatment options recurrent SCCHN.
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