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- W2890789326 abstract "3017 Background: Approximately 40-60% of metastatic cutaneous melanoma (CM) patients do not respond to the current immunotherapy (IT) regimens, pointing to other yet unknown factors conferring IT resistance. Based on our recent findings showing that germline expression quantitative trait loci (eQTLs) in immune pathways associate with overall CM survival, in this study we tested whether germline immune-specific eQTLs also impact IT outcomes in CM. Methods: By interrogating a healthy twin cohort expression dataset (MuTHER), we have identified 50 eQTLs most significantly associated with the expression of 265 immune genes. Using the MassARRAY system, these 50 SNPs were genotyped in 138 anti-CTLA-4 treated patients, 59 PD-1 treated patients and 38 patients from combined (COMBO) treatments collected from multi-institutional collaborations. To test the association of SNPs with IT response, logistic regression was performed for each treatment group adjusting by demographic and clinical covariates. Results: We found significant associations with COMBO IT resistance for rs6673928 (OR = 4.249, p = 0.0167), an eQTL in IL10/IL19 which we have recently identified for association with melanoma survival; interestingly, it is a previously established locus associated with the risk of several autoimmune diseases. Additionally, we also identified eQTLs that are associated with IT sensitivity: rs4848306 in IL1-β with resistance to anti-CTLA-4 (OR = 0.373, p = 0.000733) and rs2071304 in SPI1with resistance to anti-PD-1 (OR = 0.3328, p = 0.0271). Conclusions: In this study we report that rs6673928, an eQTL from the IL19/IL10 locus previously shown to predict autoimmunity risk and CM survival, is also a surrogate marker of response to COMBO IT. The associations of rs6673928 with both IT response and CM survival indicate a strong relationship between interleukin pathways and the level of tumor immunogenicity. In addition to its apparent function in immune response, the putative multi-faceted role of this locus in predicting better survival and IT outcomes indicates high potential as a novel clinical target. Additional genetic and functional validation of these findings is currently underway in a large collaborative setting." @default.
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- W2890789326 date "2017-05-20" @default.
- W2890789326 modified "2023-10-01" @default.
- W2890789326 title "Expression quantitative trait loci (eQTLs) as germline determinants of melanoma immunotherapy response." @default.
- W2890789326 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.3017" @default.
- W2890789326 hasPublicationYear "2017" @default.
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