A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-pronefamilies

Germline mutations within the coding region of CDKN2A have been observed in affected members of melanoma-prone families. G101W is the most common CDKN 2A missense mutation identified to date. It has been reported in several fa milies from around the world, with a particularly high occurrence in France and Italy. Given the frequency of this mutation, we were interested in det ermining whether the mutation resulted from a single origin or represented a mutational hotspot in the CDKN2A gene. rn addition, given the geographica l distribution of the mutation, we examined the date of origination of the mutation and its migratory spread. We examined 10 families from Italy, 4 fa milies from the United States, and 6 families from France with the G101W mu tation. The following eight markers were employed for the haplotype analysi s: IFNA, D9S736, D9S1749, D9S942, D9S1748, D9S1604, D9S171, and D9S126. Our findings showed no significant evidence for mutational heterogeneity, sugg esting that all studied families derived from a single ancestral haplotype on which the mutation arose. Using maximum-likelihood methods, we estimated the mutation to have arisen 97 generations ago (1-LOD-unit support interva l 70-133 generations) providing some explanation for the wide geographical spread of this common mutation, particularly in southwestern Europe. The pr esence of a founder mutation in a defined geographic area can facilitate ca rrier detection and genetic counseling and can provide an opportunity to st udy disease penetrance and the effect of environmental factors on the backg round of a common genetic susceptibility.