Exome sequencing of oral squamous cell carcinoma reveals molecular subgroups and novel therapeutic opportunities

Shih Chi Su, Chiao Wen Lin, Yu Fan Liu, Wen Lang Fan, Mu Kuan Chen, Chun Ping Yu, Wei En Yang, Chun Wen Su, Chun Yi Chuang, Wen Hsiung Li, Wen Hung Chung, Shun Fa Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

107 Scopus citations

Abstract

Oral squamous cell carcinoma (OSCC), an epithelial malignancy affecting a variety of subsites in the oral cavity, is prevalent in Asia. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. Improvement in therapeutic strategies and tailored treatment options is an unmet need. To unveil the mutational spectrum, whole-exome sequencing of 120 OSCC from male individuals in Taiwan was conducted. Analyzing the contributions of the five mutational signatures extracted from the dataset of somatic variations identified four groups of tumors that were significantly associated with demographic and clinical features. In addition, known (TP53, FAT1, EPHA2, CDKN2A, NOTCH1, CASP8, HRAS, RASA1, and PIK3CA) and novel (CHUK and ELAVL1) genes that were significantly and frequently mutated in OSCC were discovered. Further analyses of gene alteration status with clinical parameters revealed that the tumors of the tongue were enriched with copy-number alterations in several gene clusters containing CCND1 and MAP4K2. Through defining the catalog of targetable genomic alterations, 58% of the tumors were found to carry at least one aberrant event potentially targeted by US Food and Drug Administration (FDA)-approved agents. Strikingly, if targeting the p53-cell cycle pathway (TP53 and CCND1) by the drugs studied in phase I-III clinical trials, those possibly actionable tumors are predominantly located in the tongue, suggesting a better prediction of sensitivity to current targeted therapies. Our work revealed molecular OSCC subgroups that reflect etiological and prognostic correlation as well as defined the landscape of major altered events in the coding regions of OSCC genomes. These findings provide clues for the design of clinical trials for targeted therapies and stratification of OSCC patients with differential therapeutic efficacy.

Original languageEnglish
Pages (from-to)1088-1099
Number of pages12
JournalTheranostics
Volume7
Issue number5
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Ivyspring International Publisher.

Keywords

  • Driver gene
  • Exome sequencing
  • Mutational signature
  • Oral squamous cell carcinoma
  • Targeted therapy

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