<i>TERT</i> promoter mutations in actinic keratosis before and after treatment

Srinivas, Nalini; Neittaanmäki, Noora; Heidenreich, Barbara; Rachakonda, P. Sivaramakrishna; Karppinen, Toni; Grönroos, Mari; Tani, Taneli; Salmivuori, Mari; Snellman, Erna; Hemminki, Kari; Kumar, Rajiv

doi:10.1002/ijc.32878

Cited by 7 publications

(8 citation statements)

References 11 publications

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“…2,57,[75][76][77][78][79] In melanoma and nonmelanoma skin cancers, the À146C>T mutation exceeds the À124C>T in frequency, signifying differences in etiology and distinct mechanisms of mutagenesis. 78,[80][81][82][83][84][85] The CC>TT tandem mutations at À124/À125 and À138/À139 bp positions from the ATG start site create identical binding motifs, occur specifically in skin cancers and constitute about 10% of the detected TERT promoter alterations. 61,80,86,87 The À138/À139CC>TT mutation also appears infrequently in nonskin cancers as the base-change at À139 bp is reported as a rare C>T polymorphism represented by rs35550267.…”

Section: Distribution Of Somatic Tert Promoter Mutationsmentioning

confidence: 99%

“…The frequency of those mutations varies among cancer types and subtypes, with the −124C>T base‐change being overwhelmingly dominant in most cancers except for skin neoplasms 2,57,75‐79 . In melanoma and nonmelanoma skin cancers, the −146C>T mutation exceeds the −124C>T in frequency, signifying differences in etiology and distinct mechanisms of mutagenesis 78,80‐85 . The CC>TT tandem mutations at −124/−125 and −138/−139 bp positions from the ATG start site create identical binding motifs, occur specifically in skin cancers and constitute about 10% of the detected TERT promoter alterations 61,80,86,87 .…”

Section: Distribution Of Somatic Tert Promoter Mutationsmentioning

confidence: 99%

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Occurrence, functionality and abundance of the TERT promoter mutations

Rachakonda

Hoheisel

Kumar

2021

Intl Journal of Cancer

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies have resolved the discrete aspects, effects and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. Besides, the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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Section: Distribution Of Somatic Tert Promoter Mutationsmentioning

confidence: 99%

Section: Distribution Of Somatic Tert Promoter Mutationsmentioning

confidence: 99%

Occurrence, functionality and abundance of the TERT promoter mutations

Rachakonda

Hoheisel

Kumar

2021

Intl Journal of Cancer

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“…Interestingly, a recent study of 53 biopsied AK's in 29 patients, TERTp mutations were detected in 21% of the AK's; 83% of these TPM+ AK's also had increased p53 expression [87]. Treatment with daylight-mediated photodynamic therapy decreased the histologic grading of dysplasia as well as the frequency of TPM mutations and p53 expression.…”

Section: Discussionmentioning

confidence: 96%

The Safety of Oral Telomerase Activator in UV-Induced Skin Cancer with A Review of Telomerase in Aging and Skin Carcinogenesis

Burke¹,

Zhou²,

Wang³

et al. 2021

OBM Geriatr

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The supplement telomerase activator TA-65 (purified from Astragalus membranaceus) has been shown to retard cellular senescence, boost the aging immune system, and retard age-related symptoms. Lengthened telomeres retard aging, but because cancers often maintain longevity by lengthening telomeres, dietary telomerase activator might possibly increase tumorigenesis. This study investigated whether oral TA-65 effects the timing of onset and/or the incidence of skin cancers induced by UVB-irradiation and whether that possible effect is different if the oral supplementation is begun only after tumors are first detected clinically or if supplementation is begun before initiation of tumors as well as during and after the inciting UVB exposure. Three groups of ten Skh:1 hairless, nonpigmented mice exposed to UVB for twenty weeks were given (1) no supplementation, (2) TA-65 supplementation starting when the first UV-induced skin cancers were clinically observed, after which the UV exposure was terminated, and (3) TA-65 supplementation before, during, and after UV exposure (as more tumors subsequently appeared). Except for two time points when Group 3 had borderline or statistically more tumors ≥ 2mm per mouse, overall, there was no statistically significant difference in the time of onset, the incidence, or the tumor load of skin cancers with TA-65 with either timing, confirming the safety of this anti-aging supplement in this model of the most frequent human malignancy.

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“…In contrast, the functional consequence of the uncommon −138_139CC > TT subtype has not yet been investigated (Andres‐Lencina et al., 2018). Another difference between the pTERT mutation subtypes is that while the −124C > T subtype is predominant in non‐cutaneous cancers, especially those arising in tissues with a low proliferative rate (Heidenreich & Kumar, 2017); the −146C > T has been found more frequently in skin tumors, including benign skin lesions such as seborrheic keratoses (Heidenreich et al., 2017; Landi et al., 2006; Park et al., 2021), and actinic keratoses (Heidenreich et al., 2017; Srinivas et al., 2020). In addition, the −146C > T mutation subtype, in contrast to the −124C > T, leads to lower pTERT transcription levels in stem cells and different tumors (Rachakonda et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Clinical, histological, and molecular differences in melanoma due to different TERT promoter mutations subtypes. A retrospective cross‐sectional study in 684 melanoma patients

Manrique‐Silva,

David,

Maider

et al. 2023

Pigment Cell Melanoma Res

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Differences in survival according to the pTERT mutation subtypes (−124C > T, −146C > T, and tandem −138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (−124C > T, −146C > T, and tandem −138_139CC > TT). A retrospective cross‐sectional study including 684 patients was designed, and a Partial Least‐Squares Discriminant Analysis (PLS‐DA) was performed. After the PSL‐DA, it was observed that the tandem −138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the −124C > T and the −138_139 CC > TT subtypes were associated with fast‐growing melanomas (OR 0.5, CI 0.29–0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37–0.97, p = .037), compared to the −146C > T mutation. Finally, the −124C > T appeared to be more associated with the presence of TILs (non‐brisk) than the −146C > T (OR 0.6, CI 0.40–1.01, p = .05). These findings confirmed that the −124C > T and the tandem −138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the −124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem −138_139CC > TT mutations.

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TERT promoter mutations in actinic keratosis before and after treatment

Cited by 7 publications

References 11 publications

Occurrence, functionality and abundance of the TERT promoter mutations

Occurrence, functionality and abundance of the TERT promoter mutations

The Safety of Oral Telomerase Activator in UV-Induced Skin Cancer with A Review of Telomerase in Aging and Skin Carcinogenesis

Clinical, histological, and molecular differences in melanoma due to different TERT promoter mutations subtypes. A retrospective cross‐sectional study in 684 melanoma patients

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