A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families

The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations i n many but not all 9p21-linked melanoma families. Most Dutch melanoma famil ies segregate for a unique founder mutation (p16-Leiden), encoding a trunca ted nonfunctional p16 protein. The highly variable risk For p16-Leiden carr iers to develop melanoma suggests a role for other genetic and/or environme ntal Factors. We hypothesized that a 9p21 gene other than CDKN2A may be rel evant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analy sis for 9p21 was performed using microsatellite markers in six p16-Leiden f amilies originating From a founder population. p16-Leiden carriers in two f amilies shared an unexpectedly large founder haplotype (similar to 20-cM) a round CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden ca rriers from these families showed this extensive proximal haplotype compare d with melanoma-negative p16-Leiden carriers from the same families. Additi onal p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presenc e of a gene involved in melanoma susceptibility proximal of CDKN2A is corro borated by somatic deletions of 9p in tumors, which frequently do not inclu de CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked me lanoma families and guide the search for risk modifiers in melanoma develop ment.