© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 9, 758A-759,
May 3, 2000
© 2000 Oxford University Press
CORRESPONDENCE |
Re: Biologic and Biochemical Analyses of p16INK4a Mutations From Primary Tumors
Affiliation of authors: Department of Oncology/Pathology, Radiumhemmet, Karolinska Hospital and Institute, Stockholm, Sweden.
Correspondence to: Johan Hansson, M.D, Ph.D., Department of Oncology/Pathology, Radiumhemmet, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden (e-mail: Johan. Hansson{at}onkpat.ki.se).
In the September 15, 1999, issue of the Journal, Yarbrough et al. (1) report biologic and biochemical analyses of p16INK4a mutations detected in primary tumors. One of the mutants described, a substitution of leucine for the wild-type proline amino acid residue in codon 48 (P48L), has been identified in human tumor cell lines, including two human melanoma cell lines (2,3), as stated in the report. However, in addition, we have previously reported that this alteration occurs as a germline mutation in affected individuals of Swedish kindred with hereditary cutaneous melanoma (4). This kindred also has a high incidence of other malignancies.
In their report, Yarbrough et al. state that the P48L mutant leads to a p16 protein that binds to cyclin-dependent kinases cdk4 and cdk6, but it has a defect in cdk4/6-cyclin D kinase inhibition and cell cycle arrest. This result is surprising because binding of p16 to cdk4/6 normally abolishes kinase activity. Moreover, this result is in contrast to our previously published findings (5) and those of others (6,7). These three reports all show that binding of the P48L mutant p16 protein to cdk4 in vitro is abolished or severely reduced. With respect to cdk6 binding, the results of these investigations differ somewhat. Although we were unable to detect binding of the P48L mutant protein to cdk6, Castellano et al. (6) and Ruas et al. (7) showed different levels of residual cdk6 binding. Ruas et al. also demonstrated loss of growth arrest of human fibroblasts after transfection of a vector containing a complimentary DNA encoding the P48L mutant p16 protein (7). As further support for the significance of the CDKN2A P48L germline mutation for the development of hereditary cutaneous melanoma, we have demonstrated loss of the wild-type allele in a primary melanoma and a metastatic tumor in a mutation carrier belonging to the Swedish melanoma kindred (5).
The discrepancy between the results published by Yarbrough et al. and those previously presented cannot be explained at present but may relate to methodologic differences. This observation supports the need for a common standard for functional testing of CDKN2A mutations.
REFERENCES
1
Yarbrough WG, Buckmire RA, Bessho M, Liu ET. Biologic and biochemical analyses of p16INK4a mutations from primary tumors. J Natl Cancer Inst 1999;91:1569–74.
2 Liu Q, Neuhausen S, McClure M, Frye C, Weaver-Feldhaus J, Gruis NA, et al. CDKN2 (MTS1) tumor suppressor gene mutations in human tumor cell lines [published erratum appears in Oncogene 1995;11:2455]. Oncogene 1995;10:1061–7.[Medline]cancerlit;95215064
3 Pollock PM, Yu F, Qiu L, Parsons PG, Hayward NK. Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines. Oncogene 1995;11:663–8.[Web of Science][Medline]cancerlit;95380172
4
Platz A, Hansson J, Mansson-Brahme E, Lagerlof B, Linder S, Lundqvist E, et al. Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. J Natl Cancer Inst 1997;89:697–702.
5 Hashemi J, Linder S, Platz A, Hansson J. Melanoma development in relation to non-functional p16/INK4A protein and dysplastic naevus syndrome in Swedish melanoma kindreds. Melanoma Res 1999;9:21–30.[Web of Science][Medline]cancerlit;99268653
6
Castellano M, Pollock PM, Walters MK, Sparrow LE, Down LM, Gabrielli BG, et al. CDKN2A/p16 is inactivated in most melanoma cell lines. Cancer Res 1997;57:4868–75.
7 Ruas M, Brookes S, McDonald NQ, Peters G. Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information. Oncogene 1999;18:5423–34.[CrossRef][Web of Science][Medline]cancerlit;99429949
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