Nevus Size and Number Are Associated with Telomere Length and Represent Potential Markers of a Decreased Senescence <i>In vivo</i>

Bataille, Véronique; Kato, Bernet; Falchi, Mario; Gardner, J. P.; Kimura, Masayuki; Lens, Marko; Perks, Ursula; Valdes, Ana M.; Bennett, Dorothy C.; Aviv, Abraham; Spector, Tim D.

doi:10.1158/1055-9965.epi-07-0152

Cited by 122 publications

(139 citation statements)

References 38 publications

(51 reference statements)

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“…Specifically, Wnt signals that melanoblasts receive during their migration out of the neural crest may contribute to the delay of senescence and growth of nevi in utero (21)(22)(23). By extension, developmentally linked Wnt signals might contribute to preferential nevus formation in young children and adolescents (51,52), although other factors, such as declining telomere length, are also likely to be responsible for decreased proliferative potential and nevogenesis with age (13,52).…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling potentiates nevogenesis

Pawlikowski

McBryan

Tuyn

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescenceassociated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescenceassociated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

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Section: Discussionmentioning

confidence: 99%

Wnt signaling potentiates nevogenesis

Pawlikowski

McBryan

Tuyn

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The suppression of telomerase activity in melanoma cell lines induced cellular differentiation and reduced the metastatic ability [6,30]. Longer telomere length has been linked with a higher number of nevi per patient and an increased risk for cutaneous melanoma development [2,8,42,86]. It was proposed that shorter telomere length in nevi limits proliferation and promotes senescence, protecting against malignant transformation [41,86].…”

Section: Telomerase Promoter Mutations In Skin Cancersmentioning

confidence: 99%

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

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Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the "alternative mechanism of telomere lengthening" (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and nonneoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.

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“…The lack of association with atypical naevi is not surprising, as it is well established that melanocytic vs. keratinocytic tumours are characterized by different aetiopathogenetic mechanisms and different associations with environmental factors. 11,15,17,18 Individuals with lower education are at higher risk for AK. The latter observation is in line with previous studies.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for actinic keratosis in eight European centres: a case-control study

Traianou¹,

Ulrich²,

Apalla³

et al. 2012

British Journal of Dermatology

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SummaryBackground There are limited data regarding the association of actinic keratosis (AK) and other types of nonmelanoma skin cancer (NMSC); studies investigating possible correlation of AK with melanocytic naevi are even scarcer. To our knowledge, there are no data examining the risk of AK in people using specific medications. Objective To investigate constitutional and exposure risk factors leading to AK and the coexistence of AK with NMSC and melanoma. Methods A multicentre hospital-based case-control study was performed in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain, including 343 patients with actinic keratosis (AK), 409 with squamous cell carcinoma (SCC), 602 with basal cell carcinoma (BCC), 360 with invasive melanoma and 119 with in situ melanoma, and 686 control subjects. Exposures were assessed by questionnaires that were partly self-administered and partly filled out by dermatologists. Unconditional logistic regression modelling was used to assess associations including the influence of phenotypic characteristics, presence of naevi, sunexposure habits and certain drugs on AK risk. Results Differences in hair and eye coloration variably influenced the risk for AK, with red hair signifying a seven times higher risk [odds ratio (OR) 6AE9, 95% confidence interval (CI) 4AE34-11AE00), and brown -compared with blue -eyes, about a 40% reduced risk (OR 0AE61, 95% CI 0AE13-0AE92). The darker the skin phototype, the lower the risk for AK, with phototype IV exhibiting nine times less risk of developing AK. Some and many freckles on the arms were associated with an OR of 1AE8 (95% CI 1AE08-2AE81) and 3AE0 (95% CI 1AE10-3AE54), respectively, while overall number of naevi and high educational level were inversely associated with AK. Sun exposure, thiazide diuretics and cardiac drugs had a higher risk for AK. SCC was the most frequent (58%) skin neoplasm coexisting with AKs, followed by BCC (30%), melanoma in situ (12%) and invasive melanoma (6%). Conclusion In this large case-control study from across Europe the expected associations were confirmed for known risk factors. Some possible new risk factors, including cardiac and diuretic drugs, were identified, creating a new field for further investigation in future studies.

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Nevus Size and Number Are Associated with Telomere Length and Represent Potential Markers of a Decreased Senescence In vivo

Cited by 122 publications

References 38 publications

Wnt signaling potentiates nevogenesis

Wnt signaling potentiates nevogenesis

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

Risk factors for actinic keratosis in eight European centres: a case-control study

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