TERT promoter hot spot mutations are frequent in Indian cervical and oral squamous cell carcinomas

Abstract

Squamous cell carcinoma (SCC) of the uterine cervix and oral cavity are most common cancers in India. Telomerase reverse transcriptase (TERT) overexpression is one of the hallmarks for cancer, and activation through promoter mutation C228T and C250T has been reported in variety of tumors and often shown to be associated with aggressive tumors. In the present study, we analyzed these two hot spot mutations in 181 primary tumors of the uterine cervix and oral cavity by direct DNA sequencing and correlated with patient's clinicopathological characteristics. We found relatively high frequency of TERT hot spot mutations in both cervical [21.4 % (30/140)] and oral [31.7 % (13/41)] squamous cell carcinomas. In cervical cancer, TERT promoter mutations were more prevalent (25 %) in human papilloma virus (HPV)-negative cases compared to HPV-positive cases (20.6 %), and both TERT promoter mutation and HPV infection were more commonly observed in advanced stage tumors (77 %). Similarly, the poor and moderately differentiated tumors of the uterine cervix had both the TERT hot spot mutations and HPV (16 and 18) at higher frequency (95.7 %). Interestingly, we observed eight homozygous mutations (six 228TT and two 250TT) only in cervical tumors, and all of them were found to be positive for high-risk HPV. To the best of our knowledge, this is the first study from India reporting high prevalence of TERT promoter mutations in primary tumors of the uterine cervix and oral cavity. Our results suggest that TERT reactivation through promoter mutation either alone or in association with the HPV oncogenes (E6 and E7) could play an important role in the carcinogenesis of cervical and oral cancers.

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

“…In the present study, we analyzed the TERT promoter region in cervical carcinoma and CIN lesions from Italian women and we observed TERT promoter mutations in 21.8% (22/101) of cervical SCC, in 4.2% (1/24) of AC and in 1.6% (1/62) of CIN lesions. These results are in agreement with that reported by Vinothkumar et al . describing TERT promoter mutation rate of 21.4% (30/140) among Indian cervical SCC.…”

“…The recent discovery of two activating mutations within the core promoter of the TERT gene prompted the significant role of such genetic event in the development of many cancer types . In the current study, we investigated the presence of TERT promoter mutations in head and neck cancers and confirmed the high rate of hot spot nucleotide changes in oral SCC (60%), particularly in tongue tumours, and the rarity of such mutations in oropharyngeal SCC . The expression level of telomerase was comparable in HPV‐positive and HPV‐negative oropharyngeal SCC suggesting that the low expression of E6 and E7 oncoproteins, previously shown in these tumours, has little effect on the activation of TERT promoter …”

Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

“…However, hypermethylation of the TERT promoter was found to be significant in CIN3 lesions [107] and cervical cancer samples [108]. TERT promoter variants c.-146C > T and c.-124C > T were observed in 21.4% of cervical cancer patients in India, which is almost 4 times higher than the proportions reported by studies in Western populations [109].…”

Absence of the frequently reported PIK3CA,CASP8, and NOTCH1 mutations in South Indian oral cancers

“…M13 universal sequencing primer 5 0 -tgtaaaacgacggccagt-3 0 was tagged to the forward primers of all three genes for sequencing. PCR amplifications were conducted as mentioned earlier (Vinothkumar et al, 2016).…”