Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients

SIMPLE SUMMARY: The aim of this work was to investigate prognostic genetic factors in melanoma patients. Phenotypic and disease data as well as biomaterial were collected after informed consent from patients followed up in a Skin Cancer Center of a University clinic. Genome-wide analysis (GWAS) was performed with survival data of 556 melanoma patients and genetic data including more than 300,000 common polymorphisms. The SNP rs7551288 reached suggestive genome-wide significance (p = 2 × 10(−6)). This intronic variant of the DHCR24 gene is involved in the cholesterol synthesis pathway. Further analyses and a literature review suggest an important role of this locus for the clinical course of disease in melanoma patients. ABSTRACT: Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10(−6)). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.