Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance

Abstract

Oral squamous cell cancer (OSCC) is a common malignancy attributed to use of chewing smokeless tobacco and smoking. Most of the targeted strategies are based on EGFR expression and mutation; however, none of them has shown significant improvement in survival and response rates. We carried out this study to evaluate mutational profile of tobacco associated oral carcinoma with special emphasis on EGFR and its downstream events.Patients and methodsA total of 46 histologically proven cases were recruited between January 2017 and January 2019. Apart from detailed clinical and histological studies, the paraffin-embedded tissue was submitted for expression of 50 genes using Next Generation Sequencing using Ion Ampliseq Cancer Hotspot Panel v2.ResultsThe mean age of patients was 47.8 ± 10.9 years. Majority had tumors on buccal mucosa (24) and tongue (13). Nineteen of these tumors were larger than 4 cm, and 5 had adjacent site involvement. Thirty one were node positive. TP53 mutations were commonest seen in 19 followed by CDKN2A in 11, HRAS in 8, PIK3CA in 3, SMARCB1 in 2, and KIT, EGFR, BRAF, STK11, ABL1, RB1 in one case each. Concomitant TP53 mutation was identified with other mutations like CDKN2A, HRAS, KIT, PIK3CA, STK11, SMARCB1, ABL1, and RB1 making tobacco-associated OSCC as a heterogeneous mutational tumor with multiple events. A patient with TP53 mutations has poor disease free survival (47.4 vs 63% p = 0.17); however, this was not statistically significant.ConclusionThe study shows a heterogeneous mutational spectrum with multiple mutational events in OSCC. The low EGFR mutation rates and higher mutations in EGFR downstream pathways including that in TP53 and HRAS suggest that anti EGFR strategies may not succeed in these tumors and newer agents and therapeutic combinations need to be tried.

Silencing of SPP1 Suppresses Progression of Tongue Cancer by Mediating the PI3K/Akt Signaling Pathway

“… 25 There are few specific targets for tongue cancer, mainly EGFR and EGFR/Akt. 26 It is therefore important to find a specific target for tongue cancer. In our study, we determined the differential genes of SCC154 cells and normal tongue cells, and found 3 highly specific genes, SPP1, PLAU , and APP in SCC154 cells.…”

The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers

“…As reported by many oncological studies, mutations in the TP53 gene are present in more than half of human cancers [ 52 ]. TP53 is also the most frequently mutated gene in OSCC, with frequencies ranging from 35.9% to 81% [ 48 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] ( Figure 1 ). The high mutation rate is significant because TP53 mutation is believed to initiate the proliferation of mutated cells [ 62 ].…”

“…The high mutation rate is significant because TP53 mutation is believed to initiate the proliferation of mutated cells [ 62 ]. Among the various mutations observed in TP53 , missense mutations are the most common [ 48 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 63 ]. Furthermore, most TP53 mutations are located near the DNA binding domain of the protein, which is highly associated with poor prognosis [ 53 , 54 , 56 ].…”

“…The PIK3CA gene is another commonly mutated gene in OSCC [ 53 , 54 , 55 , 58 , 59 , 60 , 61 , 63 , 66 ]. The frequency ranges from 10% to 23.9%, which is less than the mutation frequency of TP53 [ 53 , 54 , 55 , 57 , 58 , 60 , 63 ]. Unlike TP53 , the PIK3CA gene mutations are commonly observed in HPV positive oral cancers [ 65 , 67 ].…”

“…Unlike TP53 , the PIK3CA gene mutations are commonly observed in HPV positive oral cancers [ 65 , 67 ]. Studies also suggested that the most common mutational hotspots of PIK3CA are located in exon 20 [ 58 , 63 , 66 ], and a regional association between the PIK3CA mutation and the tumor site (i.e., lower alveolus and lower lip) has been observed [ 58 ]. According to some studies, PIK3CA mutations may be associated with the later stages of OSCC, as PIK3CA is frequently mutated in stage IV OSCC [ 54 , 66 ].…”