TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation

Vallarelli, Andrelou Fralete Ayres; Rachakonda, P. Sivaramakrishna; André, Jocelyne; Heidenreich, Barbara; Riffaud, Laurent; Bensussan, Armand; Kumar, Rajiv; Dumaz, Nicolas

doi:10.18632/oncotarget.10634

Cited by 58 publications

(69 citation statements)

References 28 publications

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“…Furthermore, differences between previous studies and the present study may be due to the absence of investigation of LVI and necrosis in many of the above-mentioned studies. However, various molecular alterations accompanying the BRAF V600 mutation may also be features of an ordinary nevus, such as promoter mutations of telomerase reverse transcriptase (TERT) (27,28); mutations in NRAS, PTEN, CDK2NA, STK19, KIT, GNAQ, GNA11 and NF 1 genes (29)(30)(31) or undetected interactions between the BRAF V600 mutation and other signaling pathways (26). Further studies on genotypic and phenotypic alterations in specimens of primary tumours obtained from both metastatic and nonmetastatic patients may provide more information about the impact of the BRAF mutation on prognostic features of melanoma.…”

Section: Discussionmentioning

confidence: 99%

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

Can¹,

Taştekin²,

Yalta³

et al. 2018

TJPATH

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Objective: BRAF is the most common mutation in melanoma. The most common subtype is BRAF V600E, followed by V600K. Initially, the authors aimed to investigate whether clinicopathological features of melanoma are associated with BRAF mutations. We then aimed to present the relationships between the clinicopathological features and the mutated subtype (V600E vs V600K). Material and Method:61 patients with metastatic malignant melanoma (affecting the lymph node or other distant sites) were selected. Patient data regarding age at the time of diagnosis, sex, metastatic site (lymph node, distant metastasis or both) and primary tumour site were obtained from the hospital's database. Tissue samples containing at least 30% tumour cells were isolated from the specimens of 61 patients (24 samples from primary tumours and 37 from metastatic foci) for BRAF analysis. Comparisons between the BRAF V600 mutation and clinicopathological and histopathological features were performed.Results: BRAF V600 mutation was detected in 34 (55.7%) patients. The subtype was BRAF V600E in 22 (64.7%) patients, BRAF V600K in 11(32.4%) patients and BRAF V600R in 1(2.9%) patient. The crucial results of the present study may be summarized as follows: i) BRAF V600 mutation was more common in older patients and tumors with BRAF V600 mutation revealed necrosis and LVI more commonly than wild-type tumors, ii) BRAF V600K mutation was more common in older patients and BRAF V600K mutated tumors exhibited ulceration more commonly than tumors with BRAF V600E mutation (close to significant). Conclusion:The BRAF V600 mutation may have interactions with prognostic clinicoptahological features of melanoma including necrosis and lymphovascular invasion. V600K mutation may be more common than expected and may have different associations with properties of the tumor such as tumor ulceration and patient age. Investigation of the mutated subtype of the BRAF gene may therefore reveal more detailed data about the management of melanoma and may also prevent missing of candidates for BRAF inhibitor therapies.

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Section: Discussionmentioning

confidence: 99%

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

Can¹,

Taştekin²,

Yalta³

et al. 2018

TJPATH

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“…Several studies reported evidence that confirm this possibility for cooperation between TERT promoter and BRAF/RAS mutations. Vallarelli and coworkers (Vallarelli et al 2016) described that in melanoma, TERT promoter mutations provided a direct link between TERT expression and MAPK pathway activation due to BRAF or NRAS mutations via the transcription factor ETS1, that would bind to the mutated promoter leading to the re-expression of TERT. Also, in non-small-cell lung cancers (NSCLC), Liu and coworkers described that KRAS mutations increased TERT mRNA expression and telomerase activity by activating the RAS/MEK pathway, which contributes to the aggressive phenotype of NSCLC (Liu et al 2016b).…”

Section: Tert Promoter Mutations In Thyroid Cancermentioning

confidence: 99%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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“…Telomerase reverse transcriptase (TErT), a catalytic subunit of telomerase that includes an rnA component (TErC), therewithal maintains the telomere homeostasis and chromosomal integrity (15). reactivation of TErT has been detected in approximately 90% of human cancers (3,(17)(18)(19)(20). This study attempted to investigate whether immunohistochemical expression of TErT differs in neoplastic and nonneoplastic pituitary tissues and aimed to investigate whether TErT expression is related to clinicopathological features of pituitary adenomas.…”

Section: Comparisons Of Cytoplasmic Tert Expression With Clinicopathomentioning

confidence: 99%

“…It is said that higher levels of electron transport system (ETS) transcription factors induce MMP1 expression and cause tumour invasion in pituitary adenomas (1). One of the most recent reports investigating the TErT expression in malignant melanoma has concluded that mutations in TErT promoter create additional binding sites for ETS transcription factors, particularly ETS1, and finally activates the mitogen-activated protein kinase (MAPk) pathway and cell proliferation (19). PTTG1 is a member of the securin family and is highly expressed in hormonesecreting invasive pituitary adenomas (1).…”

Section: Comparisons Of Cytoplasmic Tert Expression With Clinicopathomentioning

confidence: 99%

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Tert expression in pituitary adenomas

Can

Çelık²,

Bulbul³

et al. 2017

TJPATH

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Objective: Although pituitary adenomas have benign histomorphological features, some of them may present in an aggressive manner. To predict the behaviour of these tumours, telomerase reverse transcriptase (TErT) activity in pituitary adenomas has been the subject of a few studies with contradictory results. This study aims to investigate whether immunohistochemical expression of TErT differs in neoplastic and nonneoplastic pituitary tissues and aims to investigate whether TErT expression is related to clinicopathological features of pituitary adenomas. Material and Method:The study included 48 patients who had been diagnosed with pituitary adenomas and had clinical follow-ups. nonneoplastic pituitary tissues were obtained from autopsy specimens (n=20). Immunohistochemistry for TErT antibody was performed. Both the nuclear and cytoplasmic expression of TErT antibody was noted, and total combined TErT staining was evaluated according to nuclear and cytoplasmic stainings. Results:TErT expression did not differ between neoplastic and nonneoplastic pituitary tissues. neither total (combined nuclear and cytoplasmic) TErT nor nuclear TErT expression revealed any statistically significant relationship with any of the clinicopathological features. Higher cytoplasmic TErT expression was observed in adenomas with recurrence than adenomas without recurrence (p=0.035). Conclusion:This study introduces the notion that immunohistochemical expression of TErT does not differ in neoplastic and nonneoplastic pituitary tissues. Pituitary adenomas with cytoplasmic immunohistochemical expression of TErT have significantly higher rates of recurrence. Further studies, including combined methods of immunohistochemistry and molecular analyses in larger groups, may reveal applicable results for the clinical significance of TErT in pituitary adenomas.

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TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation

Cited by 58 publications

References 28 publications

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

TERT biology and function in cancer: beyond immortalisation

Tert expression in pituitary adenomas

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