Melanoma genetics and the development of rational therapeutics

Stanford University, Stanford, California, United States
Journal of Clinical Investigation (Impact Factor: 13.22). 05/2005; 115(4):813-24. DOI: 10.1172/JCI24808
Source: PubMed


Melanoma is a cancer of the neural crest-derived cells that provide pigmentation to skin and other tissues. Over the past 4 decades, the incidence of melanoma has increased more rapidly than that of any other malignancy in the United States. No current treatments substantially enhance patient survival once metastasis has occurred. This review focuses on recent insights into melanoma genetics and new therapeutic approaches being developed based on these advances.

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    • "This is probably because genetic factors and environmental factors contribute equally to the development of melanoma. Recent studies suggested that melanoma is found more frequently in skin with intermittent sun-exposure than in skin that is not exposed or chronically exposed[53,54]. In addition, we found that thyroid cancer patients with pTERTm have a higher risk of distant metastasis that is four times greater than that of patients without pTERTm (OR = 4.01, 95% CI = 3.15 to 5.10), in line with the study done byGandofi et al.They found that pTERTm are strongly associated with tumour progression and development of distant metastasis in papillary thyroid cancer[31]. Similarly, landa et al demonstrated that pTERTm are highly prevalent in advanced thyroid cancers (51%) compared to well-differentiated tumours (22%)[55]. "
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    ABSTRACT: Background: The prevalence of telomerase reverse transcriptase (TERT) promoter mutations (pTERTm) in non-small-cell lung cancer (NSCLC) have been investigated, but the results were inconsistent. In addition, several studies have analysed the role of pTERTm in the etiology of various types of cancers, however, the results also remain inconsistent. Methods: The genomic DNA sequence of 103 NSCLC samples were analysed to investigate the frequency of pTERTm in these patients and to establish whether these mutations are associated with their clinical data. Furthermore, a meta-analysis based on previously published articles and our cohort study was performed to investigate the association of pTERTm with patient gender, age at diagnosis, metastasis status, tumour stage and cancer prognosis (5-year overall survival rate). Results: In the cohort study, 4 patients had C228T and 2 had C250T, with a total mutation frequency up to 5.8%. Significant difference of clinical data between pTERTm carriers and noncarriers was only found in age at diagnosis. In the meta-analysis, We found that pTERTm carriers in cancer patients are older than noncarriers (Mean difference (MD) = 5.24; 95% confidence interval [CI], 2.00 to 8.48), male patients were more likely to harbour pTERTm (odds Ratios (OR) = 1.38; 95% CI, 1.22 to 1.58), and that pTERTm had a significant association with distant metastasis (OR = 3.78; 95% CI, 2.45 to 5.82), a higher tumour grade in patients with glioma (WHO grade III, IV vs. I, II: OR, 2.41; 95% CI, 1.88 to 3.08) and a higher tumour stage in other types of cancer (III, IV vs. I, II: OR, 2.48; 95% CI, 1.48 to 4.15). pTERTm was also significantly associated with a greater risk of death (hazard ratio = 1.71; 95% CI, 1.41 to 2.08). Conclusions: pTERTm are a moderately prevalent genetic event in NSCLC. The current meta-analysis indicates that pTERTm is associated with patient age, gender and distant metastasis. It may serves as an adverse prognostic factor in individuals with cancers.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Melanoma is a fatal skin cancer, with increased incidence in recent years [1], [2]. Despite improvements in awareness and early detection, the mortality in patients with melanoma is still quite high [3]. "
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    ABSTRACT: The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "A lower prevalence (22%) of mutations was detected in cutaneous melanoma. Melanoma and BCC share a common carcinogenic factor: solar exposure (Chudnovsky et al., 2005). Ionizing radiation exposure is carcinogenic in BCC but not in melanoma (Dessinioti et al., 2011; Populo et al., 2012). "
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    ABSTRACT: The reactivation or re-expression of telomerase is a widespread feature of neoplasms. TERT promoter mutations were recently reported that werehypothesized to result from UV-radiation. In this retrospective study, we assessedTERT promoter mutations in 196 cutaneous basal cell carcinomas, including 102 tumors from X-irradiated patients, 94 tumors from patients never exposed to ionizing radiation treatment, and 116 melanomas.We sought to evaluate the effects of UV and X-ray irradiation onTERTmutation frequency. TERT mutations were detected in 27% of BCCs fromX-irradiated patients, 51% of BCCs from non-irradiatedpatients and 22% of melanoma patients. TERT mutations were significantly increased in non-X-irradiatedBCC patients compared withX-irradiatedBCC patients; the mutations also presented a different mutation signature. Innon-irradiated patients, TERT mutations were more frequent in BCCsof sun-exposed skin, supporting a possible causative role of UV-radiation. In melanoma, TERT promoter mutations were generally restricted to intermittent sun-exposed areas and associated with nodular and superficial spreading subtypes, increased thickness, ulceration, increased mitotic rate andBRAFV600E mutations. Our results suggest that various carcinogenic factors may cause distinct TERT promoter mutations in BCC and that TERT promoter mutations mightbe associated with a poorer prognosis in melanoma.Journal of Investigative Dermatology accepted article preview online, 01 April 2014; doi:10.1038/jid.2014.163.
    Full-text · Article · Apr 2014 · Journal of Investigative Dermatology
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