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• W2075328811 abstract "To the Editor, Approximately 40% of familial melanoma is caused by a mutation in cyclin-dependent kinase inhibitor A (CDKN2A2, p16) (Piepkorn, 2000Piepkorn M. Melanoma genetics. an update with focus on the CDKN2A (p16)/ARF tumor suppressors.J Am Acad Dermatol. 2000; 42: 705-722Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar), a tumor suppressor that acts by regulating the cell cycle via the retinoblastoma (Rb) tumor suppressor pathway (Ruas and Peters, 1998Ruas M. Peters G. The p16INK4a/CDKN2A tumor suppressor and its relatives.Biochem Biophys Acta. 1998; 1378: F115-F177Crossref PubMed Scopus (851) Google Scholar). Although the cellular and molecular functions of CDKN2A have been studied extensively, the precise mechanism by which a mutation in this gene leads to increased susceptibility to melanoma remains unclear (Scherr, 2001Scherr R. The INK4a/ARF network in tumor suppression.Nat Rev. 2001; 2: 731-737Crossref Scopus (787) Google Scholar). One possibility is that loss of CDKN2A activity results in cell-cycle dysregulation and increased melanocytic proliferation. The clinical presentation of CDKN2A mutation carriers who have increased numbers and size of nevi (dysplastic nevus syndrome) (Meyer et al., 1992Meyer L.J. Goldgar D.E. Cannon-Albright L.A. et al.Number, size, and histopathology of nevi in Utah kindreds.Cytogenet Cell Genet. 1992; 59: 167-169Crossref PubMed Scopus (14) Google Scholar;Cannon-Albright et al., 1994Cannon-Albright L.A. Meyer L.J. Goldgar D.E. et al.Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM).Cancer Res. 1994; 54: 6041-6044PubMed Google Scholar;Newton-Bishop et al., 2000Newton-Bishop J.A. Wachsmuth R.C. Harland M. et al.Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations.J Invest Dermatol. 2000; 114: 28-33Crossref PubMed Scopus (95) Google Scholar) is consistent with this hypothesis. Furthermore, the inherent genomic instability of rapidly proliferating cells would help to explain the underlying predisposition toward melanoma in these families. Proliferation studies of melanocytic lesions have been done utilizing both Ki-67 (Smolle et al., 1989Smolle J. Soyer H.-P. Kerl H. Proliferative activity of cutaneous melanocytic tumors defined by Ki-67 monoclonal antibody: a quantitative immunohistochemical study.Am J Dermatopathol. 1989; 11: 301-307Crossref PubMed Scopus (66) Google Scholar;Moretti et al., 1990Moretti S. Massobrio R. Brogelli L. et al.Ki67 antigen expression correlates with tumor progression and HLA-DR antigen expression in melanocytic lesions.J Invest Dermatol. 1990; 95: 320-324Abstract Full Text PDF PubMed Google Scholar;Rudolph et al., 1997Rudolph P. Schubert C. Schubert B. Parwaresch R. Proliferation marker Ki-S5 as a diagnostic tool in melanocytic lesions.J Am Acad Dermatol. 1997; 37: 169-178Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar;Rudolph et al., 1998Rudolph P. Tronnier M. Menzel R. et al.Enhanced expression of Ki-67, topoisomerase IIα, PCNA, p53 and p21WAF1/Cip1 reflecting proliferation and repair activity in UV-irradiated melanocytic nevi.Hum Pathol. 1998; 29: 1480-1487Abstract Full Text PDF PubMed Scopus (40) Google Scholar;Tran et al., 1998Tran T.-A. Ross J.S. Carlson J.A. Mihm M.C. Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions.Hum Pathol. 1998; 29: 1085-1090Abstract Full Text PDF PubMed Scopus (46) Google Scholar;Grossman et al., 1999Grossman D. McNiff J.M. Li F. Altieri D.C. Expression and targeting of the apoptosis inhibitor, surviving, in human melanoma.J Invest Dermatol. 1999; 113: 1076-1081https://doi.org/10.1046/j.1523-1747.1999.00776.xCrossref PubMed Scopus (339) Google Scholar;Kaleem et al., 2000Kaleem Z. Lind A.C. Humphrey P.A. et al.Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas?.Mod Pathol. 2000; 13: 217-222Crossref PubMed Scopus (58) Google Scholar) and topoisomerase II alpha (topo II) (Lynch et al., 1997Lynch B.J. Komaromy-Hiller G. Bronstein I.B. Holden J.A. Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma.Hum Pathol. 1997; 28: 1180-1188Abstract Full Text PDF PubMed Scopus (120) Google Scholar;Mu et al., 2000Mu X.C. Tran T.A. Ross J.S. Carlson J.A. Topoisomerase II-alpha expression in melanocytic nevi and malignant melanoma.J Cutan Pathol. 2000; 27: 242-248Crossref PubMed Scopus (22) Google Scholar). For studies involving common and dysplastic nevi, the proliferative indices by Ki-67 immunostaining are very low (<1%); however, the proliferation index for melanoma in situ, primary melanoma, and metastatic melanoma, is much higher (6.3%-16.0%, Figure 1), suggesting a relationship between the degree of proliferation and the aggressiveness of the tumor. The relationship between the proliferation status of melanocytic lesions and CDKN2A carrier status has never been examined. This study tests the hypothesis that carriage of a CDKN2A mutation results in a higher proliferative status in nevi taken from carriers of the mutation relative to noncarrier family member controls. The Utah melanoma kindred 1771 that was used in this study was one of the large families originally utilized to establish the melanoma susceptibility locus on chromosome 9p21 (Cannon-Albright et al., 1992Cannon-Albright L.A. Goldgar D.E. Meyer L.J. et al.Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22.Science. 1992; 258: 1148-1152Crossref PubMed Scopus (477) Google Scholar) and later to confirm the relevance of the CDKN2A mutation in familial melanoma (Kamb et al., 1994Kamb A. Shattuck-Eidens D. Eeles R. et al.Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.Nat Genet. 1994; 8: 22-26Crossref Scopus (736) Google Scholar). Of the 36 kindred members evaluated in this study, 12 were identified as CDKN2A (V126D) mutation carriers and 24 as noncarriers by haplotype and sequence analysis. The proliferation status in this study was determined by assignment of a topo II index to nevi from K1771 family members that carried or did not carry the CDKN2A mutation. Topo II is a well-established marker of cellular proliferation and has been used to establish proliferation indices in malignant and nonmalignant tissues and is analogous to Ki67/MIB1 (Rohr and Holden, 1999Rohr L.R. Holden J.A. DNA topoisomerase II-alpha expression in duct hyperplasia and in situ duct carcinoma of the breast: correlation with histologic classification of in situ duct carcinoma.Appl Immunohistochem Mol Morph. 1999; 10: 97-102Google Scholar;Willman and Holden, 2000Willman J.H. Holden J.A. Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate.The Prostate. 2000; 42: 280-286https://doi.org/10.1002/(sici)1097-0045(20000301)42:4&#60;280::aid-pros5>3.3.co;2-gCrossref PubMed Scopus (0) Google Scholar). Like Ki67/MIB1, topo II is selectively expressed in the S, G2, and M phases of the cell cycle, but unlike Ki67/MIB1 whose function is unknown, topo II is well established as an essential enzyme for DNA replication (Holden, 1999Holden J.A. DNA topoisomerase II-alpha as a marker of cell proliferation in endocrine and other neoplasms.Endocrine Pathol. 1999; 10: 97-102Crossref Scopus (8) Google Scholar). Because of these features, topo II was selected as the best representative marker of cellular proliferation. Topo II immunostaining was performed on 66 nevi removed from the 36 members of the K1771 kindred. Tissue sections were stained with hematoxylin and eosin and immunostained for topo II protein according to standard protocol (Lynch et al., 1997Lynch B.J. Komaromy-Hiller G. Bronstein I.B. Holden J.A. Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma.Hum Pathol. 1997; 28: 1180-1188Abstract Full Text PDF PubMed Scopus (120) Google Scholar;Rohr and Holden, 1999Rohr L.R. Holden J.A. DNA topoisomerase II-alpha expression in duct hyperplasia and in situ duct carcinoma of the breast: correlation with histologic classification of in situ duct carcinoma.Appl Immunohistochem Mol Morph. 1999; 10: 97-102Google Scholar;Willman and Holden, 2000Willman J.H. Holden J.A. Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate.The Prostate. 2000; 42: 280-286https://doi.org/10.1002/(sici)1097-0045(20000301)42:4&#60;280::aid-pros5>3.3.co;2-gCrossref PubMed Scopus (0) Google Scholar). Each slide was evaluated in blinded fashion by a pathologist (SRF) who rendered a diagnosis for each nevus according to a slightly modified categorical rating scheme as previously published (Piepkorn, 1990Piepkorn M. A hypothesis incorporating the histologic characteristics of dysplastic nevi into the normal biological development of melanocytic nevi.Arch Dermatol. 1990; 126: 514-518Crossref PubMed Scopus (45) Google Scholar), ranging from a banal nevus (category 1) to melanoma in situ (category 5). Category 4 nevi are those with architectural disorder (dysplastic nevi). Table I shows the number and classification of nevi in each category. To calculate the topo II index, up to 500 nevus cells were counted from the area of maximal nevus cell staining in both the junctional and/or the dermal compartment: [(number positive/up to 500) × 100]. Results were evaluated in conjunction with the kindred members' mutation status. One of the biopsies from a mutation carrier was melanoma in situ (category 5) and was excluded from the data analysis (topo II index 7.2%).Table INumber of biopsies and categorization of nevi by carrier statusMutation status# Family membersBiopsiesCategory 1Category 2Category 3Category 4Category 5 (MIS)Carrier12257 28%01 (4%)16 (64%)1 (4%)Non-carrier244117 (46%)1 (2%)1 (2%)22 (50%)0Total366624 (36%)1 (1.5%)2 (3%)38 (58%)1 (1.5%) Open table in a new tab Despite the observations that nevi from melanoma-prone kindreds are larger and more numerous, we were unable to identify differences in proliferative activity of nevi from the carrier and noncarrier groups, irrespective of the category of nevus, or whether the nevus was situated at the dermo–epidermal junction, dermis, or was compound (Table II). The topo II index for the single melanoma in situ lesion was considerably higher than any of the nevi. As can be seen in Figure 1, these data are comparable with previous proliferation studies of nevi and melanoma in situ utilizing Ki-67.Table IIAverage topo II index of nevi from mutation carriers and noncarriers# neviAverage/SD (%)Range (%)P valueTotal Carrier240.19 + 0.200–0.60.13 Non-carrier400.27 + 0.280–1.2Junctional Carrier160.31 + 0.300–0.90.52 Non-carrier250.34 + 0.300–1.0Dermal Carrier190.10 + 0.200–0.60.12 Non-carrier350.21 + 0.310–1.4 Open table in a new tab In summary, whereas the cellular proliferation index of these nevi as determined by topo II immunostaining are in keeping with the reports of other authors, the hypothesis that nevi from CDKN2A mutation carriers would be in a higher proliferative state than nevi from noncarriers could not be substantiated based on the results from this study. Although this technique was able to detect large differences in proliferation rates between nevi and melanoma in situ, among nevi there may be very small differences in proliferative capacity undetectable by topo II staining between carriers and noncarriers. These small differences, over time, could account for differences in phenotype. It also is possible that CDKN2A-mediated increases in cellular proliferation only occur in response to stimuli (such as hormonal stimulation during puberty or ultraviolet light exposure) that were not present at the time of biopsy of these lesions. Another testable hypothesis is that decreased CDKN2A activity leads to decreased cellular senescence rather than increased proliferation, ultimately leading to the dysplastic nevus phenotype. Finally, it is possible that dysplastic nevi may be similar to neurofibromas (Sawada et al., 1996Sawada S. Florell S. Purandare S.M. Ota M. Stephens K. Viskochil D. Identification of NF1 mutations in both alleles of a dermal neurofibroma.Nat Genet. 1996; 14: 110-112Crossref PubMed Scopus (138) Google Scholar), requiring a second mutation in CDKN2A before a significant change in cellular function occurs. Further investigation is underway to evaluate the role of germline CDKN2A mutation in the increased size and number of nevi and the relationship of mutation status with the increased susceptibility to melanoma. This work was supported by grants from The Skin Cancer Foundation (SRF), the Dermatology Foundation Leaders Society Dermatologist Investigator Research Fellowship (SRF), Doris Duke Charitable Foundation, Howard Hughes Medical 1nstitute, Huntsman Cancer Foundation, Veteran Affairs, and the Utah Population Database Resource. This research was supported by the Utah Cancer Registry, which is funded by Contract # NC1-PC-67000 from the National Cancer 1nstitute with additional support from the Utah Department of Health and the University of Utah. We also thank Susan L. Neuhausen for her thoughtful comments regarding this manuscript." @default.
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• W2075328811 title "Failure to Detect Differences in Proliferation Status of Nevi from CDKN2A Mutation Carriers and Non-Carriers" @default.
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