Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance

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.

Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer

“…Fourteen mutations were observed in 7 genes across 12 of 22 samples (Supplementary Table S1). Of note, inactivating NOTCH1 mutation (4%) were found at a lower frequency in our sample set than that reported from the Caucasian population [7, 8, 20] but consistent with similar finding from a recent Asian study [21, 22]. In further contrast to Caucasian population, we observed Notch family receptors, ligands, and downstream effector genes were amplified or over expressed in 59% samples (17 of 29 patients) based on copy number variations called from whole- exome and whole- transcriptome data.…”

Molecular profile of tongue cancer in an 18‐year‐old female patient with no recognizable risk factor

“…The amplification in this patient's tumor of PIK3CA, CARD11, and SRSF2 and the loss of SMAD2 are mutations that have been reported in other cases of TSCC . Furthermore, amplification of 3q in the region containing the squamous lineage transcription factors TP63 and SOX2, and the oncogene PIK3CA are some of the molecular changes reported in HNSCC which may contribute to the development of the tumor in this patient.…”

Malignant transformation rate of oral leukoplakia in an Australian population

“…Unfortunately, there are few high‐quality genomic studies investigating early‐onset OSCC to shed light on this issue, and those to date which have focused on tongue SCC have not found much age‐based distinction. A Singaporean study found a tendency towards increased mutations in PIK3CA and MLL2 / KMT2A in late‐onset versus early‐onset OSCC whilst another US‐based study found minimal genomic differences between the two groups …”

“…The transformed patients in this cohort were aged above 55 years, although Patient 1 was substantially younger than the overall cohort, having developed OSCC at 40 years of age. This patient is part of a growing cohort of patients developing OSCC at a younger age, earlier than the time the impact of risk factors such as smoking would be expected to manifest. This suggests a potential genetic basis for the propensity of such OPMDs to transform.…”