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MARIETTA BIOL 309 - Recent advances in melanoma research

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Journal of Dermatological Science 26 (2001) 1–13Review articleRecent advances in melanoma researchToshiaki Saida *Department of Dermatology, Shinshu Uni6ersity School of Medicine,3-1-1Asahi, Matsumoto390-8621, JapanReceived 14 December 2000; accepted 18 December 2000AbstractRecent advancement in the research of malignant melanoma is reviewed. Among many gene alterations detected inhuman melanoma, defect of CDKN2A located at chromosome 9p21 seems to be most important in the earlierdevelopmental phase, though significance of this gene in the evolution of melanoma in situ has not been confirmedyet. Deletions of PTEN/MMAC1on 10q23.3 and AIM1on 6q21 as well as mutations of ras gene are involved in thelater progression stages of melanoma. Adhesion molecules relevant to development and progression of melanomahave been intensely investigated in recent years, revealing crucial roles of cadherins and avb3integrin in the biologicbehaviors 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 amajor concern in this field. Fragility of blood vessels in melanoma lesions is another important point related tohematogeneous metastases. Acral lentiginous melanoma is a unique subtype of melanoma, because, in contrast toother subtypes, ultraviolet irradiation is not a major factor in its development. Investigation of pathogenesis of acrallentiginous 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 expressionprofile is introduced, which possibly enables us to give the tailor-made therapy for each melanoma patient in the nearfuture. © 2001 Elsevier Science Ireland Ltd. All rights reserved.Keywords:Malignant melanoma; Pathogenesis; Gene alterations; Molecular events; New treatmentwww.elsevier.com/locate/jdermsci1. IntroductionIncidence of malignant melanoma is rapidlyincreasing particularly in white populations. Alsoin Japan, number of melanoma patients has obvi-ously increased in recent years. Major advanceshave been made not only in basic research butalso in clinical management of this highly malig-nant neoplasm. In this article, the author reviewsthe advancement in melanoma research, givingsome personal comments on each topic.* Tel.: +81-263-372643; fax: + 81-263-372646.E-mail address:[email protected] (T. Saida).0923-1811/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.PII: S0923-1811(01)00085-8T. Saida/Journal of Dermatological Science26 (2001) 1– 1322. Molecular events in melanoma development andprogressionRecently, great advances have been made in theresearch of molecular biology of malignantmelanoma [1– 5]. These advances surely lead us tobetter understanding of the mechanisms involvedin the development and progression of this neo-plasm. Moreover, based on these advances, morerational management of patients with melanomawill be invented.2.1. Genetic alterations in malignant melanomaOne of major recent advances in melanomaresearch is identification of cytogenetic and ge-netic alterations responsible for its developmentand progression. Disruptions of many genes havebeen detected on a variety of chromosomes. Thefollowings are updated information about themain genes relevant to pathogenesis of melanoma.2.1.1. CDKN2A(P16)Linkage analysis of familial melanoma sug-gested presence of a melanoma susceptibility geneon chromosome 9p21[6,7]. Loss of heterozygosity(LOH) at 9p21 regions was also detected fre-quently in cultured human melanoma cells [8]. Inaddition, a non-familial melanoma patient whocarried somatic germline defect at 9p21 developedmultiple melanomas [9]. Soon later, CDKN2A(cyclin-dependent kinase inhibitor 2A) gene, alsocalled MTS1, residing on this locus was suspectedto be the melanoma susceptibility gene [10,11].This gene encodes p16 or INK4a (inhibitor ofkinase 4a), which inactivates CDK4 (cyclin-de-pendent kinase 4) through competing with cyclinD1 for binding of CDK4 [12]. Cycline D1/CDK4complexes phosphorylate and thus inactivate RB(retinoblastoma gene product), resulting in thedissociation of the E2F factors, transcription fac-tors required for expression of S phase genes.Therefore, CDKN2A plays an important role atthe G1 checkpoint of the cell cycle and thus, sameas RB, CDKN2A is considered as a tumor sup-pressor gene [2,3,7].Germline mutations in CDKN2A are found inapproximately 50% of 9p-linked melanoma-pronefamilies [7]. Most of the mutations are found onexons 1a and 2; frame shift, nonsense or missensemutations, inframe deletions, and insertions re-sulting in production of non-functional proteins[2]. Some of the family members suffer also frompancreatic carcinoma [13]. Mutation or deletionat the CDKN2A locus is detected in  70% ofcultured melanoma cell lines and in  35% ofuncultured melanoma cells. Methylation of thepromoter region of the gene is considered asanother suppression mechanism of CDKN2A [14].These data indicate involvement of CDKN2A inmelanoma development. LOH analysis suggestedthat deletion of CDKN2A was one of the earliestevents in melanoma development, as the deletionwas detected in invasive primary lesions with thintumor thickness [15]. Related to the mutations ofCDKN2A, it is interesting that a germline muta-tion of CDK4gene located on 12q13 was found ina few melanoma-prone families [16]. The mutatedgene product, CDK4(Arg24Cys), is defective inbinding to p16, but hold the ability to bind cyclinD. Cytotoxic T cells (CTLs) recognizing the mu-tated CDK4 were detected in a few melanomapatients. Taken together, disruptions ofCDKN2A/CDK4pathway surely play a majorrole in melanoma development.Multiple atypical nevi (dysplastic nevi, Clark’snevi) are frequently observed in the members ofmelanoma-prone families. However, relationshipbetween CDKN2A and atypical nevi has not beenyet determined. In a 9p-linked melanoma familyreported by Puig et al. [17], only two out of 10individuals with atypical nevi showed the muta-tion of CDKN2A. They suggested that a generesponsible for development of atypical nevus wasdifferent from CDKN2A. In familial melanomakindreds reported by Hussussian et al., 92% (33/36) of melanoma


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