TERT Promoter Mutations Are Enriched in Oral Cavity Cancers and Associated With Locoregional Recurrence

PURPOSE Telomerase reverse transcriptase ( TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)–negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P < .001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P < .001) and in the overall cohort (Gray's test, P < .001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P = .0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted.

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TERT promoter mutations are associated with poor prognosis in cutaneous squamous cell carcinoma

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2018.08.032 ◽

2019 ◽

Vol 80 (3) ◽

pp. 660-669.e6 ◽

Cited By ~ 7

Author(s):

Manuel António Campos ◽

Sofia Macedo ◽

Margarida Fernandes ◽

Ana Pestana ◽

Joana Pardal ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Poor Prognosis ◽

Cutaneous Squamous Cell Carcinoma ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder

Modern Pathology ◽

10.1038/modpathol.2016.53 ◽

2016 ◽

Vol 29 (5) ◽

pp. 511-515 ◽

Cited By ~ 20

Author(s):

Morgan Cowan ◽

Simeon Springer ◽

Doreen Nguyen ◽

Diana Taheri ◽

Gunes Guner ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Urinary Bladder ◽

Cell Carcinoma ◽

Squamous Cell ◽

Primary Squamous Cell Carcinoma ◽

Tert Promoter ◽

High Prevalence ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Clinical and molecular classification of vulvar squamous pre-cancers

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2018-000135 ◽

2019 ◽

Vol 29 (4) ◽

pp. 821-828 ◽

Cited By ~ 9

Author(s):

Paul A Cohen ◽

Lyndal Anderson ◽

Lois Eva ◽

James Scurry

Keyword(s):

Squamous Cell Carcinoma ◽

Next Generation Sequencing ◽

Cell Carcinoma ◽

Squamous Cell ◽

Intraepithelial Neoplasia ◽

Vulvar Intraepithelial Neoplasia ◽

Next Generation ◽

Vulvar Squamous Cell Carcinoma ◽

Increased Risk ◽

Generation Sequencing

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.

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TERT Promoter Mutations Are Frequent in Cutaneous Basal Cell Carcinoma and Squamous Cell Carcinoma

PLoS ONE ◽

10.1371/journal.pone.0080354 ◽

2013 ◽

Vol 8 (11) ◽

pp. e80354 ◽

Cited By ~ 51

Author(s):

Klaus G. Griewank ◽

Rajmohan Murali ◽

Bastian Schilling ◽

Tobias Schimming ◽

Inga Möller ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Basal Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Basal Cell ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Heterogeneity of TERT promoter mutations status in squamous cell carcinomas of different anatomical sites

Annals of Diagnostic Pathology ◽

10.1016/j.anndiagpath.2015.03.005 ◽

2015 ◽

Vol 19 (3) ◽

pp. 146-148 ◽

Cited By ~ 22

Author(s):

Katherine A. Cheng ◽

Boaz Kurtis ◽

Sabina Babayeva ◽

Jian Zhuge ◽

Irlna Tantchou ◽

...

Keyword(s):

Squamous Cell ◽

Squamous Cell Carcinomas ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms20061333 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1333 ◽

Cited By ~ 4

Author(s):

Alessandra Ventura ◽

Cristina Pellegrini ◽

Ludovica Cardelli ◽

Tea Rocco ◽

Valeria Ciciarelli ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Telomerase Activity ◽

Cutaneous Squamous Cell Carcinoma ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Telomere Biology ◽

Promoter Mutations

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

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