The purpose of the project is to reverse the trend of increasing incidense and reduce mortality in melanoma by increasing the knowledge about individuals' genetically determined risks of developing melanoma and response to treatment. Melanoma is a tumor disease that affects more and more people and still over 500 persons die each year due to melanoma in Sweden. It is therefore of great importance to improve the possibilities for preventive interventions and early diagnostics when the prognosis is most favorable and to treat people the most effective way. In one sub-project, we want to investigate if polygenic risk scores (PRS) can be used as a tool to identify individuals at increased risk for melanoma beyond that identified from traditional risk factors. We have genotyped 67 SNVs, significantly associated to melanoma in large genome-wide association studies (GWAS), in approximately 600 melanoma patients, including both familial melanoma patients and sporadic melanoma patients (with single or multiple primary melanomas). We have also genotyped a smaller subset of control individuals (N=200, mainly blood donors). Preliminary data show that melanoma patients has significantly higher PRS than the control individuals. Here, the inclusion of the SweGen data would be a valuable addition to increase the power of the study. We want to extract genotypes of the 67 SNVs from the whole-genome data (stored at Bianca) from the 1000 individuals included in the SweGen project and calculate their PRS to be used as a larger control cohort. Our aim with this study is to improve future preventive and screening guidelines, which subsequently can halt the concerning trend of increasing melanoma incidence. We are also investigating the effect of host genotype factors on response to treatment. Immune checkpoint inhibitors (ICIs) have emerged as effective treatments in metastatic melanoma. The tumor mutational burden has been established as a strong independent predictive factor for efficacy of ICIs. Further, inherited variants of the melanocortin 1 receptor (MC1R) gene have been shown to influence the somatic mutation burden in melanoma. MC1R plays a crucial role in pigmentation regulation, encoding the receptor protein that mediates melanogenesis. Certain germline variants in MC1R (designated R alleles) are accountable for deficient melanin production, and therefore associated with red hair color, freckling and melanoma susceptibility. Our study is the first to address whether inherited polymorphisms in MC1R affect the efficacy of ICIs in melanoma patients.        We have collected 103 advanced melanoma patients undergoing ICIs treatment and genotyped them for germline MC1R variants. The patients were grouped by the presence or absence of germline MC1R R variants (≥1 or 0) and followed-up for treatment response, progression-free survival (PFS) and overall survival (OS). We have also retrieved FFPE sections for 25 melanoma metastases from these patients for whole-exome sequencing in parallel with their corresponding germline DNA. We aim to further characterize their mutation burdens, co-occurring genetic alterations in order to evaluate germline MC1R variants as predictive markers for ICI in melanoma patients.