Original contributionExpression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients☆
Section snippets
Tissue samples
A total of 98 formalin-fixed, paraffin-embedded lesions were collected from patients belonging to melanoma kindreds. Samples came from pathology units in Italy, Sweden, and Australia, and all assays were performed in the same laboratory in Italy. In detail, 49 lesions came from the Department of Pathology at San Martino Hospital and 9 came from the Department of Pathology at the National Institute for Cancer Research, both in Genova. One lesion was provided by the San Gallicano Hospital in
Mutational analysis of CDKN2A in familial melanoma patients
Of the 37 families from Italy, Sweden, and Australia analyzed for CDKN2A status, 25 were found to be mutation-positive. Twelve of the 24 Italian families had no mutations, and 12 carried the G101W mutation (2 of which had not been described previously). The 9 Australian families carried a variety of mutations13 in either exon 1 (9del24, 33ins24, L16P, R24P, L32P, and G35A) or exon 2 (M53I), and the 4 families from Sweden carried the 113insR mutation12 (Table 1).
Specificity and establishment of reproducible conditions for all antibodies
Lesions were tested with at
Discussion
Because the progression stages of melanoma have been well characterized, genetic studies are essential for the development of a model of melanoma pathogenesis.18 The INK4a/ARF locus encodes 2 cell cycle regulatory proteins, the CDK inhibitor p16INK4a and the p53 activator p14ARF. Alterations affecting this locus occur in familial melanoma kindreds and cause functional and quantitative defects in p16 and p14 expression.5 Although the role of CDKN2A has been widely studied, few efforts have been
Acknowledgements
The authors thank L. Luzzatto for advice and critical reading of the manuscript, and P. Grammatico and A. Amantea for providing a lesion from a mutated patient. Special thanks to S. Gargiulo for helping to prepare sections from Italian patients, M. Mantelli and L. Pastorino for providing technical assistance, and L. V. Battistuzzi for assisting in the preparation of the manuscript.
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2014, CellCitation Excerpt :p16 lacks an identifiable NLS and may enter the nucleus by diffusion, and is detectable in both the cytoplasm and nucleus. However, p16(M53I) is mainly nuclear in vivo in melanocytic lesions of familial melanoma patients (Ghiorzo et al., 2004). Passive transport alone cannot lead to nuclear accumulation (Kim and Elbaum, 2013).
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2011, Clinics in Laboratory MedicineCitation Excerpt :The final signature change of melanoma to be described concerns the tumor suppressor gene CDK2NA, which is located on chromosome 9p21and encodes p16INK4a and, via an alternate reading frame, p14ARF. Mutation, methylation, and deletion of the CDKN2A gene is well described in both sporadic and familial melanomas, and is found in around 80% of cases.30–34 Melanoma-associated CDKN2A mutations and deletions can involve p16INK4a, p14ARF, or both transcripts.
High frequency of p16 INK4A promoter methylation in NRAS-mutated cutaneous melanoma
2010, Journal of Investigative DermatologyCitation Excerpt :Three of these had both a monoallelic deletion and carried a mutation in the coding region. We and others have found that p16INK4A mutation-positive tumors express the protein although it has been shown that some of these point mutations impair the function of p16INK4A protein (Ghiorzo et al., 2004b; Scaini et al., 2009). In addition (Yang et al., 2005) predicted the effects of 117 reported CDKN2A point mutations showing large variations regarding the impact on p16INK4A protein.
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2009, Weedon's Skin Pathology: Third Edition
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Supported by grants FIRB post genoma RBNE014975 2001, Ministry of Health ICS 030.1/RF99.32, and AIRC 2002 (to G.B.S.); grants from the Cancer Society of Stockholm, the King Gustav V Jubilee Fund, the Karolinska Institute Research Funds, and the Swedish Radiation Protection Institute (to J.H. and A.P.); and funding from the National Health and Medical Research Council of Australia (to N.H.)