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Introduction
Melanoma is most common in populations with European ancestry. The highest incidence rates are reported from Australia and New Zealand with more than 50/100,000 new cases and 6/100 000 deaths per year compared to around 20/100,000 new cases and 3/100 000 deaths in Western Europe. Established host risk factors are the total body naevus number, fair skin and a family history of melanoma. In the last decade several new genetic loci identified through genome-wide association analyses (GWAS) were shown to influence pigmentation traits and melanoma risk. Recently an intronic SNP in PPARGC1B has been shown to modify tanning ability and melanoma survival. The aims of this thesis were to conduct phenotypic and genetic comparisons of early and late stage melanoma patients, and to compare melanoma patients from Brisbane, Australia and Tübingen, Germany. This included associations of PPARGC1B and PPARGC1A coding polymorphisms with pigmentation traits, melanoma risk and progression in both these populations.
Methods
Two cohorts of melanoma patients and controls from Tübingen (n=614) and Brisbane (n=893) have been collected and analysed to investigate phenotypes and genotypes associated with melanoma risk and progression. Data and material included questionnaires, clinical assessments, melanoma specific parameters and germline DNA. Genotyping was performed by Sanger Sequencing, TaqMan SNP assays and with a high throughput Illumina CoreExome Chip assay. Phenotype and genotype associations were analysed using cross tabulation and logistic regression models. Survival probabilities were assessed genome-wide and for single variables using Kaplan Meier estimates, and comparisons were done with the log rank test.
Results
Patients with high naevus counts had no favourable outcome in the analysed cohort from Tübingen, however being a carrier of a MC1R r allele was associated with an improved survival probability (p=0.049). Two SNPs, the intronic variants rs7551288 in DHCR24, and rs12146110 in USH2A, were found in a genome-wide association analyses to be associated with overall survival and furthermore with progression in stage IV (p<0.001). Melanoma patients from Brisbane had favourable prognostic tumour characteristics and a higher rate of familial and multiple melanomas compared to patients from Tübingen. Further-more, the influence of the PPARGC1 transcription factors (PGC-1) on pigmentation was investigated. The exon SNP rs3736265 (T612M) in PPARGC1A was found for the first time to reduce naevus count. The intronic SNPs rs251468 and rs32579 in PPARGC1B were both confirmed to increase tan-ning ability and decrease naevus count, the SNP rs32579 additionally to improve survival in a meta-analysis.
Conclusion
Genetic variants have been identified that influence pigmentation traits, melanoma risk and progression. New loci of potential relevance for naevus count, melanoma risk and progression have reached statistical significance. UV radiation has an overriding influence on the impact of genetic predisposition, especially in countries with high UV exposure and is leading to an increase of preventable, initially less aggressive melanomas.
UV protection, early recognition and early treatment remain the most important strategies to overcome the rise of preventable melanomas and to reduce melanoma deaths. |
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