Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0219-2) contains supplementary material, which is available to authorized users.
Highlights
Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival
Most of the unique genes detected here were not seen in the International Cancer Genome Consortium (ICGC) study, which focused on an Indian population with tobacco- and betel nut-associated Oral squamous cell carcinoma (OSCC)-GB, reinforcing the need to carry out similar studies in different populations
Even after correcting for these accuracy data, the differences observed between our cohort and The Cancer Genome Atlas (TCGA) remains significant. Further validation of this approach can be inferred from the fact that we found similar frequencies of mutations in a number of genes previously detected by TCGA, including USH2A, FAT1, PLEC, SYNE1, PIK3CA, MLL2/KMT2A, MLL3/ KMT2C, CASP8 COL6A6, and ZFHX4
Summary
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. Oral squamous cell carcinoma (OSCC) accounts for 270,000 new cancer cases and 145,000 deaths annually, the majority of which occur in developing countries [1]. Two-thirds are oral tongue squamous cell carcinoma (OTSCC) [2, 3]. Current treatment strategies involve a multimodality approach involving surgery, chemotherapy, and radiotherapy. Despite advances in detection and treatment, 5-year overall. There appears to have been a shift in epidemiology towards a higher proportion of never-smokers and younger patients, with an increase in incidence among women [5,6,7,8,9]. The basis of this epidemiological trend remains elusive, what is definitely worrisome is that the cancers arising in this
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