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 in many but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. We hypothesized that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analysis for 9p21 was performed using microsatellite markers in six p16-Leiden families originating from a founder population. p16-Leiden carriers in two families shared an unexpectedly large founder haplotype ( approximately 20-cM) around CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden carriers from these families showed this extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers from the same families. Additional p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do not include CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked melanoma families and guide the search for risk modifiers in melanoma development.
van der Velden
P A
PA
MGC-Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Sandkuijl
L A
LA
Bergman
W
W
Hille
E T
ET
Frants
R R
RR
Gruis
N A
NA
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004416:Dysplastic Nevus Syndrome / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010375:Pedigree; D012307:Risk Factors
D019941:Cyclin-Dependent Kinase Inhibitor p16; D005819:Genetic Markers