MARIETTA BIOL 309 - Recent advances in melanoma research (13 pages)

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Recent advances in melanoma research



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Journal of Dermatological Science 26 2001 1 13 www elsevier com locate jdermsci Review article Recent advances in melanoma research Toshiaki Saida Department of Dermatology Shinshu Uni6ersity School of Medicine 3 1 1 Asahi Matsumoto 390 8621 Japan Received 14 December 2000 accepted 18 December 2000 Abstract Recent advancement in the research of malignant melanoma is reviewed Among many gene alterations detected in human melanoma defect of CDKN2A located at chromosome 9p21 seems to be most important in the earlier developmental phase though significance of this gene in the evolution of melanoma in situ has not been confirmed yet Deletions of PTEN MMAC1 on 10q23 3 and AIM1 on 6q21 as well as mutations of ras gene are involved in the later progression stages of melanoma Adhesion molecules relevant to development and progression of melanoma have been intensely investigated in recent years revealing crucial roles of cadherins and avb3 integrin in the biologic behaviors of melanoma cells Melanoma is characterized by extremely high potential of developing metastases Dynamic changes of matrix metalloproteinase activity during invasion and movement of melanoma cells may be a major concern in this field Fragility of blood vessels in melanoma lesions is another important point related to hematogeneous metastases Acral lentiginous melanoma is a unique subtype of melanoma because in contrast to other subtypes ultraviolet irradiation is not a major factor in its development Investigation of pathogenesis of acral lentiginous melanoma surely provides us with new information about mechanism of melanocyte transformation Recent advances in the management of malignant melanoma are also briefly reviewed such as biochemotherapy immunotherapy and gene therapy Finally the concept of molecular classification of melanoma by gene expression profile is introduced which possibly enables us to give the tailor made therapy for each melanoma patient in the near future 2001 Elsevier Science Ireland Ltd All rights reserved Keywords Malignant melanoma Pathogenesis Gene alterations Molecular events New treatment 1 Introduction Incidence of malignant melanoma is rapidly increasing particularly in white populations Also Tel 81 263 372643 fax 81 263 372646 E mail address tosaida hsp md shinshu u ac jp T Saida in Japan number of melanoma patients has obviously increased in recent years Major advances have been made not only in basic research but also in clinical management of this highly malignant neoplasm In this article the author reviews the advancement in melanoma research giving some personal comments on each topic 0923 1811 01 see front matter 2001 Elsevier Science Ireland Ltd All rights reserved PII S 0 9 2 3 1 8 1 1 0 1 0 0 0 8 5 8 2 T Saida Journal of Dermatological Science 26 2001 1 13 2 Molecular events in melanoma development and progression Recently great advances have been made in the research of molecular biology of malignant melanoma 1 5 These advances surely lead us to better understanding of the mechanisms involved in the development and progression of this neoplasm Moreover based on these advances more rational management of patients with melanoma will be invented 2 1 Genetic alterations in malignant melanoma One of major recent advances in melanoma research is identification of cytogenetic and genetic alterations responsible for its development and progression Disruptions of many genes have been detected on a variety of chromosomes The followings are updated information about the main genes relevant to pathogenesis of melanoma 2 1 1 CDKN2A P16 Linkage analysis of familial melanoma suggested presence of a melanoma susceptibility gene on chromosome 9p21 6 7 Loss of heterozygosity LOH at 9p21 regions was also detected frequently in cultured human melanoma cells 8 In addition a non familial melanoma patient who carried somatic germline defect at 9p21 developed multiple melanomas 9 Soon later CDKN2A cyclin dependent kinase inhibitor 2A gene also called MTS1 residing on this locus was suspected to be the melanoma susceptibility gene 10 11 This gene encodes p16 or INK4a inhibitor of kinase 4a which inactivates CDK4 cyclin dependent kinase 4 through competing with cyclin D1 for binding of CDK4 12 Cycline D1 CDK4 complexes phosphorylate and thus inactivate RB retinoblastoma gene product resulting in the dissociation of the E2F factors transcription factors required for expression of S phase genes Therefore CDKN2A plays an important role at the G1 checkpoint of the cell cycle and thus same as RB CDKN2A is considered as a tumor suppressor gene 2 3 7 Germline mutations in CDKN2A are found in approximately 50 of 9p linked melanoma prone families 7 Most of the mutations are found on exons 1a and 2 frame shift nonsense or missense mutations inframe deletions and insertions resulting in production of non functional proteins 2 Some of the family members suffer also from pancreatic carcinoma 13 Mutation or deletion at the CDKN2A locus is detected in 70 of cultured melanoma cell lines and in 35 of uncultured melanoma cells Methylation of the promoter region of the gene is considered as another suppression mechanism of CDKN2A 14 These data indicate involvement of CDKN2A in melanoma development LOH analysis suggested that deletion of CDKN2A was one of the earliest events in melanoma development as the deletion was detected in invasive primary lesions with thin tumor thickness 15 Related to the mutations of CDKN2A it is interesting that a germline mutation of CDK4 gene located on 12q13 was found in a few melanoma prone families 16 The mutated gene product CDK4 Arg24Cys is defective in binding to p16 but hold the ability to bind cyclin D Cytotoxic T cells CTLs recognizing the mutated CDK4 were detected in a few melanoma patients Taken together disruptions of CDKN2A CDK4 pathway surely play a major role in melanoma development Multiple atypical nevi dysplastic nevi Clark s nevi are frequently observed in the members of melanoma prone families However relationship between CDKN2A and atypical nevi has not been yet determined In a 9p linked melanoma family reported by Puig et al 17 only two out of 10 individuals with atypical nevi showed the mutation of CDKN2A They suggested that a gene responsible for development of atypical nevus was different from CDKN2A In familial melanoma kindreds reported by Hussussian et al 92 33 36 of melanoma patients had CDKN2A mutations but only 30 10 33 of atypical nevi patients had the


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