Multiple melanomas after treatment for Hodgkin lymphoma in a non-Dutch p16-Leiden mutation carrier with 2 MC1R high-risk variants.
BACKGROUND
A 19-base pair germline deletion in exon 2 of the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene (Leiden mutation) has been detected in Dutch families with familial melanomas. The penetrance of CDKN2A mutations varies widely and is influenced by environmental and unrelated genetic factors such as variants in the MC1R gene.


METHODS
We describe a 25-year-old German woman who developed 8 invasive melanomas and 6 in situ melanomas after radiation therapy and polychemotherapy for Hodgkin lymphoma. Genetic testing revealed a constitutional CDKN2A Leiden mutation in the proband and her sister, mother, and mother's sister. The proband also carried high-risk MC1R variant alleles R151C and R160W, which she had inherited from her father and her mother, respectively. The less affected mutation carrier sister did not have high-risk MC1R variant alleles. Analysis of DNA from paraffin-embedded tissues showed loss of heterozygosity at CDKN2A loci in all 3 melanomas studied but not in Hodgkin lymphoma. The pedigree revealed several types of cancers on both sides of the family, but no Dutch ancestors were found. No mutations in the CDK4, B-raf, and N-ras genes were detected either in the germline or in tumors from the patient.


CONCLUSIONS
This study shows the variability of the penetrance of the CDKN2A Leiden mutation within the same family, which could be due to genetic or exogenous factors.
Figl
Adina
A
Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
Thirumaran
Ranjit K
RK
Ugurel
Selma
S
Gast
Andreas
A
Hemminki
Kari
K
Kumar
Rajiv
R
Schadendorf
Dirk
D
D000328:Adult; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006689:Hodgkin Disease / Q000235:genetics / Q000628:therapy*; D006801:Humans; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D044102:Receptor, Melanocortin, Type 1