Frequent<i>TERT</i>Promoter Mutations in Ocular Surface Squamous Neoplasia

Scholz, Simone L.; Thomasen, Henning; Reis, Henning; Möller, Inga; Darawsha, Raid; Müller, Bettina; Dekowski, Dirk; Sucker, Antje; Schilling, Bastian; Schadendorf, Dirk; Steuhl, Klaus‐Peter; Paschen, Annette; Westekemper, Henrike; Meller, Daniel; Griewank, Klaus G.

doi:10.1167/iovs.15-17469

Cited by 26 publications

(12 citation statements)

References 43 publications

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“…The pattern of TERT promoter mutations identified in our Ugandan conjunctiva neoplasia cohort is similar to that previously described in conjunctiva SCC of German patients as well as in melanoma and non-melanoma skin cancers [ 17 , 18 , 29 , 30 ]. Interestingly, the occurrence of TERT promoter mutations in 37.5% of CIN1 observed in our results suggests that the UV-induced DNA damage may precede the progression of conjunctiva early lesions to high grade neoplasia.…”

Section: Discussionsupporting

confidence: 84%

“…The solar UV radiation exposure is the main cause of the most common skin cancers, such as basal cell carcinoma, cutaneous SCC, cutaneous melanoma and other epithelial tumours such as conjunctiva neoplasia [ 27 , 28 ]. The frequency of C>T or CC>TT UV-related mutations in TERT promoter region has been found similarly high in basal cell carcinoma (56%), cutaneous SCC (50%), cutaneous melanoma (up to 71%) and conjunctiva neoplasia (43.8%), [ 16 – 18 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…The hot spot nucleotide changes − 124G>A and − 146G>A in TERT promoter have been detected at high frequency in cancers of internal organs, such as bladder cancer, hepatocellular carcinoma, thyroid cancer, and gliomas [ 15 , 35 , 36 ]. In contrast, tandem mutations CC>TT are related to the UV mutagenic activity and very rarely identified in tumours of internal organs [ 13 , 29 , 35 , 35 – 39 ]. In our study CC>TT substitutions in TERT promoter were very frequent in accordance with their overall frequency in other UV-related tumours [ 16 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Telomerase promoter mutations in human immunodeficiency virus-related conjunctiva neoplasia

2018

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BackgroundSquamous cell carcinoma (SCC) of the conjunctiva is a common cancer in Africa mainly associated with solar ultraviolet (UV) exposure and human immunodeficiency virus (HIV) infection. We analyzed the role of HIV on the occurrence of telomerase reverse transcriptase (TERT) promoter mutations among a cohort of conjunctiva neoplasia Ugandan patients.MethodsTelomerase reverse transcriptase promoter mutations were searched in 72 conjunctiva neoplasia cases, comprising SCC and intraepithelial neoplasia grade 1–3 (CIN1–3), as well as in 53 conjunctiva normal tissues and in 24 HIV-related Kaposi sarcoma.ResultsThe average prevalence of TERT promoter mutations in conjunctiva neoplasia was 31.9%. The mutation rates were significantly higher in HIV-positive (31.8% of CIN1 and CIN2, 46.2% of CIN3 and SCC,) than HIV-negative patients (22.2% of CIN1 and CIN2, 13.3% of CIN3 and SCC). Such mutations were rarely identified among HIV-positive conjunctiva controls (3.6%) and never in Kaposi sarcoma lesions. The most frequent variations were the hot spots − 124G>A and − 146G>A and tandem transitions − 124_125GG>AA and − 138_139GG>AA.ConclusionsTelomerase reverse transcriptase promoter mutations are early events in conjunctival neoplasia and could be used for timely diagnosis of conjunctiva tumours. The high frequency of UV-signatures in HIV-positive conjunctiva lesions suggests an additive effect of the virus to UV-related mutagenesis.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Telomerase promoter mutations in human immunodeficiency virus-related conjunctiva neoplasia

2018

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“…However, one of the key events reported are mutations affecting the tumor suppressor gene p53, with a high percentage of CC > TT alterations, which confirms the causative role of solar rays in the etiology of the tumor [ 50 ]. Moreover, Scholz et al identified mutations in the telomerase reverse transcriptase (TERT) gene promoter—a marker of other systemic cancers [ 51 ] and a sign of worse prognosis [ 52 , 53 ]—in 44% of the 48 samples of conjunctival OSSN included in their study [ 54 ]. Finally, hyper-expression of matrix metalloproteinases MMP-9 and MMP-11 and hypo-expression of clusterin seem to be a hallmark in the tumor cell transcriptome [ 55 ].…”

Section: Risk Factors and Pathogenesismentioning

confidence: 99%

Clinical Management of Ocular Surface Squamous Neoplasia: A Review of the Current Evidence

et al. 2018

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Ocular surface squamous neoplasia (OSSN) is the most common non-pigmented malignancy of the ocular surface and is represented in a wide range of histologic diagnoses, ranging from mild epithelial dysplasia to invasive squamous carcinoma. Although surgical excision is still the gold standard for OSSN treatment, interest in conservative medical approaches is steadily growing. We have reviewed all of the literature on OSSN published in English in the MEDLINE database up to May 2018, using the keywords “ocular surface squamous neoplasia,” “squamous conjunctival carcinoma,” and “conjunctival carcinoma in situ,” with the aim to provide a comprehensive review of the most recent evidence on this distinct clinical entity.

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“…Scholz et al examined clinicopathological factors and biomarkers and identified promoter mutations in telomerase reverse transcriptase in 44% of 48 samples of conjunctival OSSN associated with ultraviolet light induction [5]. Recent research demonstrated that PD-L1 is expressed in almost half of conjunctival SCC cases and noted the potential application of immune checkpoint blockade as a treatment strategy for conjunctival SCC [6].…”

Section: Introductionmentioning

confidence: 99%

Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment

et al. 2020

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Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. Methods In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. Results All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival.

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FrequentTERTPromoter Mutations in Ocular Surface Squamous Neoplasia

Cited by 26 publications

References 43 publications

Telomerase promoter mutations in human immunodeficiency virus-related conjunctiva neoplasia

Telomerase promoter mutations in human immunodeficiency virus-related conjunctiva neoplasia

Clinical Management of Ocular Surface Squamous Neoplasia: A Review of the Current Evidence

Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment

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