Background: Carcinoma 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. Methods: Seventy-eight cases were subjected to whole-exome (n = 18) and targeted deep sequencing (n = 60). Results: While 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. Conclusions: Our 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.
Bibliographical noteFunding Information:
We would like to thank all our patients and their families who contributed to this study. This project is funded through grants from National Cancer Centre Research Foundation, Singhealth Foundation (SHF/FG452P/2011) and National Medical Research Council (Singapore) Clinician-Scientist Award (NMRC/CSA/042/2012) to NGI. This work was also supported by funding from Duke-NUS, NUHS, and CSI Singapore to PT. This research is also supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.
© 2015 Vettore et al.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology