NOVEL GERMLINE P16 MUTATION IN FAMILIAL MALIGNANT-MELANOMA IN SOUTHERN SWEDEN

The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-str anded conformation polymorphism analysis of all three exons and flanki ng intron regions followed by sequence analysis, A novel germline muta tion, constituting an in-frame 3-bp duplication at nucleotide 332 in e xon 2, was identified in two families (Lund M2 and M9). The mutation r esults in an insertion of Arg at codon 105, which interrupts the last of the four ankyrin repeats of the p16 protein, motifs which have been demonstrated as important in binding and inhibiting the activity of c yclin D-dependent kinases 4 and 6 in cell cycle G(1) phase regulation. All five tested individuals of Lund M2 and Mo affected by melanoma we re mutation carriers, as were five melanoma-free individuals, Other ma lignancies observed in gene carriers or obligate carriers included cer vical, breast, and pancreatic carcinomas and a non-Hodgkin's lymphoma, Analysis of microsatellite markers adjacent to the p16 gene at chromo somal region 9p21 revealed that both families share a common haplotype , in keeping with a common ancestor.