Absence of BRAF mutations in UV-protected mucosal melanomas

Edwards, Robin

doi:10.1136/jmg.2003.016667

Cited by 173 publications

(118 citation statements)

References 12 publications

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“…BRAF mutation has previously been reported to be rare among patients with primary mucosal melanoma. 20 In contrast, three of four patients with primary mucosal melanoma exhibited BRAF mutation in the present study.…”

Section: Discussioncontrasting

confidence: 48%

Analysis of BRAF Mutation in Primary and Metastatic Melanoma

Libra¹,

Malaponte²,

Navolanic³

et al. 2005

Cell Cycle

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Mutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.

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Section: Discussioncontrasting

confidence: 48%

Analysis of BRAF Mutation in Primary and Metastatic Melanoma

Libra¹,

Malaponte²,

Navolanic³

et al. 2005

Cell Cycle

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“…18 Some reports have shown a relationship between the type of sun exposure and the alterations affecting the BRAF-RAS pathway. [19][20][21] A higher frequency of BRAF mutations has been found in cutaneus melanomas arising in intermittent sun-exposed sites with respect to the lesions developing in mucosal membranes or unexposed sites. 22 On the contrary, RAS alterations are more common in skin sites subjected to chronic sun exposure.…”

Section: Brafmentioning

confidence: 99%

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

et al. 2008

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BRAFV600E mutation has been frequently reported in different types of melanocytic lesions, but its role in melanomagenesis is poorly understood, having been associated with either the proliferative-induced MAPK pathway activation or the acquisition of oncogene-driven senescence. The presence of BRAF alterations has been related to sun exposure, although the molecular mechanisms underlying this event are only partly known. To elucidate the relationships among BRAF/NRAS alterations, MAPK pathway activation, and sun exposure, we examined 22 acquired nevi and 18 cutaneus melanomas from 38 patients. Microdissected tissues from each lesion were subjected to BRAF/NRAS mutation analysis by sequencing, allele-specific PCR and pyrosequencing assay. The same lesions were also examined for the expression of phosphorylated ERK1/2. Phototype and an accurate history of sun exposure were evaluated for each patient. BRAF V600E mutation was detected in 50% of the acquired nevi and in 70% of the cutaneus melanomas in the absence of NRAS alterations. The fraction of alleles carrying BRAF V600E substitution was variable but strongly associated with sun exposure. In contrast, no relationship was evidenced between the presence of this mutation and patients' phototype, phosphorylated ERK1/2 expression, or Clark's level. Our findings indicate that in melanocytic lesions, BRAF V600E mutation can affect a subset of the cells and is associated with the type and quantity of sun exposure. This mutation is independent of the nevo-melanoma progression and unrelated to ERK phosphorylation, suggesting that alternative mechanisms to the MAPK activation are also involved in this type of transformation.

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“…Specifically, BRAF mutations are common (59%) in melanomas arising in skin with intermittent sun exposure, such as trunk and arms, compared with only 23% of the acral melanomas and 11% of mucosal melanomas harboring BRAF mutations (Maldonado et al 2003;Edwards et al 2004;Curtin et al 2005), but are absent in uveal melanoma (Cohen et al 2003;Cruz et al 2003;Edmunds et al 2003;Rimoldi et al 2003;. A clear understanding of the UV-BRAF link is further complicated by the observation that melanomas from chronically sun-exposed areas (defined by histopathological evidence of chronic sun damage) possess only an 11% frequency of BRAF V600E mutation (Maldonado et al 2003;Edwards et al 2004;Curtin et al 2005). Together, these contrasting observations highlight the uncertainties surrounding the molecular factors driving BRAF mutation, in particular, the role of sun exposure.…”

Section: The Ras Family Of Proto-oncogenes: H-ras N-ras and K-rasmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Absence of BRAF mutations in UV-protected mucosal melanomas

Cited by 173 publications

References 12 publications

Analysis of BRAF Mutation in Primary and Metastatic Melanoma

Analysis of BRAF Mutation in Primary and Metastatic Melanoma

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

Malignant melanoma: genetics and therapeutics in the genomic era

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