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Mutation analysis of candidate genes in melanoma-prone families: evidence of different pathogenetic mechanisms at chromosome 9p21

Casula, Milenaa; Ascierto, Paolo Ab; Cossu, Antonioc; Sini, Maria Ca; Tore, Silviaa; Colombino, Mariaa; Satta, Maria Pa; Manca, Antonellaa; Rozzo, Carlaa; Satriano, Sabrina MRb; Castello, Giuseppeb; Lissia, Ameliac; Tanda, Francescoc; Palmieri, Giuseppea


Putative tumour suppressor genes CDKN2A and CDKN2B (on chromosome 9p21) and CDKN2A-interacting cell growth regulatory genes CDK4 and Id-1 have been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). Mutation analysis of these candidate genes was performed in MM families from southern Italy with three or more affected members or two affected members and one or more relative with histologically diagnosed atypical naevus. Two CDKN2A mutations, Arg24Pro and 1292 G>A, were observed in two (15%) families; except for CDKN2A and Id-1 polymorphisms, no sequence variations were detected in the remaining genes. Screening among 119 sporadic MM cases revealed two additional CDKN2A mutations at very low prevalences. Identification of a large shared haplotype at 9p21 in some MM families negative for CDKN germline mutations suggests that other CDKN-inactivating mechanisms may be responsible for MM predisposition or, alternatively, additional susceptibility gene(s) may be present on chromosome 9p21. Fluorescence in situ hybridization analysis of a subset of MM tissue sections seemed to indicate that the D9S171 locus may be involved in MM pathogenesis.

aIstituto di Chimica Biomolecolare, CNR, Alghero, 07040 Santa Maria La Palma (Sassari), Italy, bIstituto Nazionale Tumori ‘Fondazione G. Pascale', Napoli, Italy, and cIstituto di Anatomia Patologica, Università di Sassari, Sassari, Italy.

Sponsorship: This work was supported by Ricerca Finalizzata Ministero della Sanità (FSN), Regione Autonoma della Sardegna Progetto ‘Genetica e Tumori nel Nord Sardegna', and Associazione Italiana Ricerca sul Cancro.

Correspondence and requests for reprints to Giuseppe Palmieri, Istituto di Chimica Biomolecolare-Sezione di Sassari, Località Tramariglio-Alghero, 07040 Santa Maria La Palma (Sassari), Italy. Tel: +39 079 946 706; fax: +39 079 946 714; e-mail:

Received 18 March 2003 Accepted 23 July 2003

© 2003 Lippincott Williams & Wilkins, Inc.