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Genome Medicine

, 7:98

First Online: 23 September 2015Received: 09 April 2015Accepted: 25 August 2015


BackgroundCarcinoma of the oral tongue OTSCC is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention.

MethodsSeventy-eight cases were subjected to whole-exome n = 18 and targeted deep sequencing n = 60.

ResultsWhile the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent. Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC. Importantly, these Notch pathway alterations were prognostic on multivariate analyses. A high proportion of OTSCCs also presented with alterations in drug targetable and chromatin remodeling genes. Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials.

ConclusionsOur study defines the Asian OTSCC mutational landscape, highlighting the key role of Notch signaling in oral tongue tumorigenesis. We also observed somatic mutations in multiple therapeutically relevant genes, which may represent candidate drug targets in this highly lethal tumor type.

AbbreviationsCIconfidence interval

DFSdisease-free survival

EGFRepidermal growth factor receptor

GATKGenome Analysis Tool Kit


GSEAGene Set Enrichment Analysis

HNSCChead and neck squamous cell carcinoma

HPVhuman papillomavirus

HRhazard ratio

ICGCInternational Cancer Genome Consortium

IGVIntegrative Genomics Viewer

indelinsertion or deletion

MAPKmitogen-activated protein kinase

NPVnegative predictive value

OCoral cavity

OSoverall survival

OSCCoral squamous cell carcinoma

OTSCCoral tongue squamous cell carcinoma

PCRpolymerase chain reaction

PPVpositive predictive value

SNVsingle-nucleotide variation

TCGAThe Cancer Genome Atlas

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-015-0219-2 contains supplementary material, which is available to authorized users.

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Autor: Andre Luiz Vettore - Kalpana Ramnarayanan - Gregory Poore - Kevin Lim - Choon Kiat Ong - Kie Kyon Huang - Hui Sun Leong


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