<i>BRAF</i> Gene Is Somatically Mutated but Does Not Make a Major Contribution to Malignant Melanoma Susceptibility: The Italian Melanoma Intergroup Study

Casula, Milena; Colombino, Maria; Satta, Maria Paola; Cossu, Antonio; Ascierto, Paolo A.; Bianchi‐Scarrǎ, Giovanna; Castiglia, Daniele; Budroni, Mario; Rozzo, Carla; Manca, Antonella; Lissia, Amelia; Carboni, A.; Petretto, E; Satriano, S.M.R.; Botti, Gerardo; Mantelli, Michela; Ghiorzo, Paola; Stratton, Michael R.; Tanda, F; Palmieri, Giuseppe

doi:10.1200/jco.2004.07.112

Cited by 54 publications

(41 citation statements)

References 21 publications

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“…BRAF does not appear to be an inherited cancer predisposition gene (Laud et al 2003;Casula et al 2004;Jackson et al 2005;Kelemen et al 2005;Xing 2005), as individuals with germline mutations develop instead cardio-facio-cutaneous syndrome, which is not associated with increased cancer risk (Niihori et al 2006;Rodriguez-Viciana et al 2006). The high prevalence of BRAF mutations in cutaneous melanoma and the known epidemiological link between UV and melanoma has prompted speculation that the BRAF V600E mutation is induced by UV damage.…”

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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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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“…Studies of melanoma patients have revealed little evidence that BRAF is a melanoma susceptibility gene (Lang et al, 2003;Laud et al, 2003;Meyer et al, 2003a;Jackson et al, 2005). There is only one report on two germline mutations (M116R and Q608H) in three individuals (Casula et al, 2004). In a BRAF E600 knock-in mouse model, expression of BRAF E600 in all tissues results in embryonic lethality by day E7.5, making it unlikely that this mutation would be compatible with life in humans (Mercer et al, 2005).…”

Section: Melanoma Susceptibility and Braf Mutationsmentioning

confidence: 99%

BRAFE600 in benign and malignant human tumours

et al. 2007

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Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF E600 -expressing human tumour cells. Although BRAF E600 acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF E600 signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF E600 in benign and malignant human tumours and the implications for therapeutic intervention.

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“…A study of 569 Italian cases had identified 1 germ-line case of the V600E variant (17 ), but these data were subsequently retracted (27 ). The same study found 2 types of germ-line variants that were previously unreported codon changes (M116R, Q608H).…”

Section: Brafmentioning

confidence: 98%

“…Only 1 common germ-line coding variant has been observed, however, and it is a silent change (G643G) in exon 16, which is unlikely to have functional consequences. Nevertheless, a recent study reported 3 different germline variants in melanoma cases from Italy, including 1 case of V600E (17 ) that prompted us to analyze our large case-control collection.…”

Section: Brafmentioning

confidence: 99%

Rapid Screening of 4000 Individuals for Germ-line Variations in the BRAF Gene

et al. 2006

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Background:The BRAF gene is frequently somatically altered in malignant melanoma. A majority of variations are at the valine 600 residue leading to a V600E substitution that constitutively activates the kinase. We screened 4000 patient and control DNAs for germ-line variations at the valine 600 residue. Methods: We developed a novel assay by adapting single-base variation assays and software for MALDI-TOF (matrix-assisted laser desorption/ionization timeof-flight) mass spectrometry to screen for all 5 reported variants at codon 600 of the BRAF gene. We screened a case-control collection comprising samples from 1082 melanoma patients and 154 of their unaffected relatives from 1278 families and from 2744 individuals from 659 unselected twin families with no history of melanoma. A panel of 66 melanoma cell lines was used for variation-positive controls. Results: All melanoma cell lines that we had found previously to carry a codon 600 variation were verified in this study. Three of the 4 possible variants (V600E n ‫؍‬ 47, V600K n ‫؍‬ 2, V600R n ‫؍‬ 1) were detected, but no case of V600D was available. No germ-line variants were found in the samples from the 3980 melanoma patients or from the control individuals. Conclusions: This new assay is a high-throughput, automated alternative to standard sequencing and can be used as a rapid initial screen for somatic variants associated with melanoma. Germ-line variants at valine 600 are unlikely to exist and do not contribute to the reported role of the BRAF gene in melanoma predisposition.

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BRAF Gene Is Somatically Mutated but Does Not Make a Major Contribution to Malignant Melanoma Susceptibility: The Italian Melanoma Intergroup Study

Cited by 54 publications

References 21 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

BRAFE600 in benign and malignant human tumours

Rapid Screening of 4000 Individuals for Germ-line Variations in the BRAF Gene

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