Telomerase promoter mutations in cancer: an emerging molecular biomarker?

João Vinagre, Vasco Pinto and Ricardo Celestino contributed equally to the manuscript.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 non-neoplastic 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

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene

Teledermatology - the requirements of dermatologists in private practice

Eighty-four dermatologists in private practice in Bavaria were surveyed by postal questionnaire. Of the 45 who responded (a 54% response rate), 96% used a computer in their private practice. Fifty-seven per cent of respondents owned systems with Pentium processors, while 23% were still using 386 or 486 processors. Most of them used the Windows 95, UNIX or Apple operating system. Of the respondents who had a modem, 74% used ISDN. There were few modems connected to the ordinary telephone network. Of all respondents, 56% used email regularly. Several possible teledermatology applications were proposed in the survey (i.e. teleconsultation, on-line/off-line videoconferencing, email attachments). Fifty-six per cent of respondents said that they would perform teleconsultations with dermatology clinics, 40% preferred a teleconsultation via telephone and computer, and 42% sending files via email. The survey demonstrated that a high proportion of dermatologists in private practice would use a teledermatology service

Mixed Capillary/Lymphatic Malformation with Coexisting Port-Wine Stain: Treatment Utilizing 3D MRI and CT-Guided Sclerotherapy

BACKGROUND. Lymphatic malformation, a benign malformation of the skin and the subcutaneous tissues, is divided into two major groups: the classical and the localized forms. Pathologically lymphatic malformation often consists of sequestered lymphatic cisterns with thick muscle walls lying deeply in the subcutaneous tissue. Communicating via dermal lymphatic channels with superficial pseudovesicles, they can vary in size depending on the pressure transmitted by the cisterns beneath. METHODS. We present a patient with mixed capillary/lymphatic malformation and coexisting port-wine stain since birth. To demonstrate the anatomic extent and the subcutaneous involvement we performed a 3D reconstruction of a magnetic resonance imaging (MRI). The diagnostic procedures, therapeutic possibilities, and complications regarding this rare appearance are reviewed. RESULTS. Good results could be obtained with CO2 laser vaporization of the superficial lesions and computed tomography (CT)-guided transcutaneous sclerotherapy for the deeper cisterns with doxycycline. CONCLUSION. The combination of CO2 laser treatment and sclerotherapy with doxycycline seems to present a treatment option for cutaneous and subcutaneous lymphangioma circumscriptum with rare side effects