A melanoma-associated germline mutation in exon 1β inactivates p14ARF

Rizos, Helen; Puig, Susana; Badenas, Cèlia; Malvehy, Josep; Darmanian, Artur; Jiménez, Laura; Milá, Montserrat; Kefford, Richard

doi:10.1038/sj.onc.1204728

Cited by 169 publications

(102 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, in the present case, a pathogenic effect of this mutation is suggested by several data. Specific p14 ARF germline defects were previously reported in a family with melanoma and neural tumours and in a patient with multiple melanomas (Randerson-Moor et al, 2001;Rizos et al, 2001b). In addition, some of the INK4a-ARF germline mutations found in melanomaprone families have been shown to affect p14 ARF function (Rizos et al, 2001a).…”

Section: Discussionmentioning

confidence: 86%

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

et al. 2004

View full text Add to dashboard Cite

Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient o25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.

show abstract

Section: Discussionmentioning

confidence: 86%

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Several studies also implicated the ARF gene as underlying melanoma predisposition. A 16 bp insertion in exon 1b, which affects the function of p14 but not p16, was described in a patient with multiple primary melanomas (Rizos et al, 2001). A splice site mutation in exon 1b, which results in p14 haploinsufficiency, was also reported in two affected persons from melanoma kindred (Hewitt et al, 2002).…”

Section: Discussionmentioning

confidence: 91%

Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours

et al. 2005

View full text Add to dashboard Cite

To gain insight into the molecular mechanisms involved in the inherited predisposition to melanoma and associated neural system tumours, 42 Jewish, mainly Ashkenazi, melanoma families with or without neural system tumours were genotyped for germline point mutations and genomic deletions at the CDKN2A/ARF and CDK4 loci. CDKN2A/ARF deletion detection was performed using D9S1748, an intragenic microsatellite marker. Allele dosage at the p14 ARF locus was analysed by quantitative real-time PCR employing a TaqMan probe that anneals specifically to exon 1b of the p14 ARF gene. For detecting point mutations, dHPLC and direct sequencing of the coding sequences of CDKN2A/ARF and CDK4 was used. No germline alterations in any of the tested genes were detected among the families under study. We conclude that in the majority of Ashkenazi Jewish families, the genes tested are unlikely to be implicated in the predisposition to melanoma and associated neural system tumours.

show abstract

“…Although insertions and deletions in ARF exon 1␤ without affecting INK4A or INK4B expression have been reported in melanoma cell lines (Kumar et al 1998), the most convincing data on ARF as an independent melanoma suppressor came from two melanoma patients with germline ARF-specific mutations. One patient harbored a 14-kb deletion in exon 1␤ sparing both INK4A and INK4B genes (Randerson-Moor et al 2001), while the second patient had a 16-bp insertion in exon 1␤ generating a frame-shifted ARF mutant defective in cell cycle arrest (Rizos et al 2001). However, intact INK4A activity was not demonstrated in either case, precluding definitive assignment of INK4A-independent activity to ARF.…”

Section: Arf-mdm2-p53 Pathwaymentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

View full text Add to dashboard Cite

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...

show abstract

A melanoma-associated germline mutation in exon 1β inactivates p14ARF

Cited by 169 publications

References 37 publications

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours

Malignant melanoma: genetics and therapeutics in the genomic era

Contact Info

Product

Resources

About