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Novel Germline p16 Mutation in Familial Malignant Melanoma in Southern Sweden¹

Departments of Oncology [Å. B., U. J., O. J., S. H., H. O.], Surgery [J. W., C. I.], and Pathology [A. M.], University Hospital, S-221 85 Lund, Sweden

The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-stranded conformation polymorphism analysis of all three exons and flanking intron regions followed by sequence analysis. A novel germline mutation, constituting an in-frame 3-bp duplication at nucleotide 332 in exon 2, was identified in two families (Lund M2 and M9). The mutation results 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 cyclin D-dependent kinases 4 and 6 in cell cycle G₁ phase regulation. All five tested individuals of Lund M2 and M9 affected by melanoma were mutation carriers, as were five melanoma-free individuals. Other malignancies observed in gene carriers or obligate carriers included cervical, breast, and pancreatic carcinomas and a non-Hodgkin's lymphoma. Analysis of microsatellite markers adjacent to the p16 gene at chromosomal region 9p21 revealed that both families share a common haplotype, in keeping with a common ancestor.

¹ This study was supported by grants from the Swedish Cancer Society; the Mrs. Berta Kamprad Foundation; the Medical Faculty University of Lund; the Cancer & Trafikskadades Riksförbund; the Gunnar, Arvid, and Elisabeth Nilsson Cancer Foundation; and the Crafoord Foundation.

² To whom requests for reprints should be addressed. Phone: (46) 46 177569; Fax: (46) 46 147327; E-mail: ake.borg@onk.lu.se.

Received 3/ 4/96. Accepted 4/11/96.

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