title: MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma.
abstract: The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR-restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma.
authors.affiliation: Departments of aClinical and Experimental Medicine, Division of Cell Biology bClinical and Experimental Medicine, Division of Dermatology cClinical and Experimental Medicine, Division of Experimental Pathology dClinical and Experimental Medicine, Division of Environmental and Occupational Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Lena K
authors.initials: LK
authors.lastname: Thunell
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bivik
authors.forename: Petra
authors.initials: P
authors.lastname: Wäster
authors.forename: Mats
authors.initials: M
authors.lastname: Fredrikson
authors.forename: Annika
authors.initials: A
authors.lastname: Stjernström
authors.forename: Ingrid
authors.initials: I
authors.lastname: Synnerstad
authors.forename: Inger
authors.initials: I
authors.lastname: Rosdahl
authors.forename: Charlotta
authors.initials: C
authors.lastname: Enerbäck
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2