DELETION MAPPING OF CHROMOSOME REGION 9P21-P22 SURROUNDING THE CDKN2 LOCUS IN MELANOMA

The cyclin-dependent kinase-4 inhibitor gene CDKN2, localized at chrom osome region 9p21, has been shown to be a familial melanoma gene, thou gh we found that mutations of it are rare in uncultured sporadic melan omas. To determine whether the region of allelic loss at 9p21 frequent ly observed in sporadic melanomas includes the CDKN2 locus, new polymo rphic microsatellite probes were isolated from the genomic segments su rrounding the CDKN2 gene and used for the study of loss of heterozygos ity (LOH) in melanoma. The LOH study of matched uncultured tumor-const itutional DNA pairs from 66 metastatic cutaneous and 19 primary uveal melanomas showed that 63% and 32% of the respective tumors suffered al lelic loss in the 9p21 region. Two regions of common losses which did not include the CDKN2 locus were observed: in a region of common loss near the D9S157 locus, telomeric to the CDKN2 locus, deletions were ob served in 51% of informative cases; in the other region of common loss , near the D9S171 locus, centromeric to the CDKN2 locus, deletions wer e observed in 47% of informative cases. At the D9S974 locus, located w ithin 20 kb of the CDKN2 gene, deletions were observed in 43% of infor mative cases. Homozygous deletions of the CDKN2 locus were observed in 8 cases of cutaneous melanoma and 2 cases of uveal melanoma; mutation s in CDKN2 exon 2 were found in 2 of the 46 cases with allelic deletio n in 9p21. Our results support the following conclusions: (i) somatic mutation of the CDKN2 gene is rare in sporadic melanomas with allelic loss at 9p21; (ii) homozygous loss is move frequent than mutation of t he CDKN2 gene in sporadic melanomas; (iii) at 9p21-p23 genes other tha n CDKN2 may be involved in the development of sporadic melanomas. (C) 1996 Wiley-Liss, Inc.