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. 2017 Feb 26;7(5):1088-1099.
doi: 10.7150/thno.18551. eCollection 2017.

Exome Sequencing of Oral Squamous Cell Carcinoma Reveals Molecular Subgroups and Novel Therapeutic Opportunities

Shih-Chi Su  1   2 , Chiao-Wen Lin  3   4 , Yu-Fan Liu  5 , Wen-Lang Fan  1 , Mu-Kuan Chen  6 , Chun-Ping Yu  7 , Wei-En Yang  8   9 , Chun-Wen Su  8   9 , Chun-Yi Chuang  10   11 , Wen-Hsiung Li  7 , Wen-Hung Chung  1   2   12 , Shun-Fa Yang  8   9
Affiliations

Exome Sequencing of Oral Squamous Cell Carcinoma Reveals Molecular Subgroups and Novel Therapeutic Opportunities

Shih-Chi Su et al. Theranostics. .

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.

Keywords: Oral squamous cell carcinoma; driver gene; exome sequencing; mutational signature; targeted therapy..

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Conflict of interest statement

Competing interest: The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Mutational signatures of 120 oral cancers (A) Five mutational signatures were deciphered in the OSCC cohort and corresponding to the updated consensus signatures . Mutation types are shown in different colors on the horizontal axis. The vertical axis illustrates the percentage of mutations attributed to a specific mutation type. (B) Tumor classification (mutational signature cluster, MSC) based on the contributions of mutational signatures. The fraction and number of mutations attributed to each signature in each tumor is represented by the colored bars below the dendogram. (C) Clinicopathological and etiological characteristics associated with each MSC group.
Figure 2
Figure 2
Significantly altered genes in OSCC (A) Mutation rate, demographic and clinical features, environmental exposures and landscape of genomic alterations of 120 OSCC patients. Patients exposed to environmental risks are indicated as a filled square. *, subjected to whole-genome sequencing; #, germline POLD1 mutation. (B) Frequency of SCNAs along the genome. The vertical axis indicates the frequency of SCNAs in the cohort. Selected genes in recurrent amplifications and deletions are labeled. (C) Correlation of gene alteration status with demographic and clinical parameters. *p < 0.05, **p < 0.01, ***p < 0.001, χ2 test for trends in proportion.
Figure 3
Figure 3
Co-occurrence of gene alterations reveals major groups of associated aberrations. (A) The size of gene indicates the alteration frequency. Significant associations between genes are represented with the darkness of width of the lines. Colors for each gene signify its involvement in a particular pathway. (B) Heat map of altered groups of genes in 120 OSCC.
Figure 4
Figure 4
The landscape of major altered genes and potentially druggable pathways in OSCC. Pills show targets of pharmaceuticals (FDA-approved agents or drugs screened in clinical trials). Genes assigned to each pathway are represented with their alteration frequencies (red font, protein-altering mutation; while font, amplification; yellow font, copy loss), and promotive or inhibitory regulations between genes are highlighted.
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