Predicting a mutation in the melanoma predisposing gene CDKN2A

BestPractice | Sept 2019 | Dermatologi |

Around 10 % of new melanoma cases show a familial association. The most important predisposing gene so far characterized is CDKN2A associated with a penetrance of melanoma of 70% by age 80. While 40% develop multiple melanomas, an increased risk for pancreatic cancer and upper airway tumours are also seen.1-3 The risk of pancreatic cancer has been especially high in Dutch and Swedish mutation carrying families.  Both in Holland and in Sweden a founder mutation account for vast majority of cases In Holland p-16Leiden (c.225:243del,p.ALA 76Cysfs*64 ) and in Sweden (c335_337dupl, p,Arg 112 dup).4 The origin of the Swedish founder mutation has been traced to the northern part of the county Småland with an approximate age of the mutation 2000 years (98 generations 95% CI: 52 - 167 ).5 In Sweden so far around 80 families have been identified.  In families with a CDKN2A mutation non carriers also have an increased melanoma risk being phenocopies.6 This could be due to presence of modifying other genes or that family members share environmental exposures such as to UV-light.  In Swedish families with melanoma where no CDKN2A mutation is found family members only have a risk for non-melanoma skin tumours and melanomas.7 It has not been possible by histopathology to identify mutation carriers although a family history of melanoma is more common in cases with truncal and nodular melanoma.8-9 In collaboration with Dutch researchers we have therefore developed a risk score (CM-score) for predicting the presence of a CDKN2A mutation using number of family members (first and second degree) with melanoma, number of family members (first and second degree) with multiple melanomas, median age at primary diagnosis, presence of pancreatic cancer, and presence of upper airway cancer.1 Below is the scoring system (CM-score) and the results shown. (adopted from Potjer et al JMG...