Abstract 1212: Quantitative ancestry analysis in Hispanic uveal melanoma patients reveals novel disease susceptibility loci
Authors: Rodriguez Daniel Alexander , Sanchez Margaret I. , Decatur Christina L. , Harbour J. William 
Published: September 2020

Uveal Melanoma (UM) is the most common eye cancer in adults and leads to metastatic death in up to half of patients. The molecular landscape of UM has been extensively characterized, and this information is now widely used in clinical management. Research interest in UM has expanded dramatically in the past decade, with landmark genomic studies highlighting its unique and deadly clinical and molecular characteristics however this pool of genetic data has been performed almost entirely in white non-Hispanic patients of European ancestry. Hispanics are the second most common ethnic group affected by UM, and one of the fastest growing ethnic groups in the U.S. Individuals who self-identify as Hispanic. This study included 141 patients with posterior uveal melanomas, 72 who self identified as White non-Hispanic, 61 as Hispanic, 4 as Black non-Hispanic, 2 as Asian non-Hispanic, and 2 as Other/Multiracial non-Hispanic. In order to by-pass ethnic and cultural variables that influence self reporting demographic information, global and local ancestry was assessed. Leukocyte DNA from each patient was genotyped, generating whole genome single nucleotide polymorphism (SNP) profiles. Quality control was performed keeping only bi allelic SNPs and SNP call rate of &gt;98%. Global ancestral estimates, using greater than 100,000 SNPs, were calculated against reference samples from West African, East Asian, European, and Native American ancestral populations. ADMIXTURE was used to estimate the ancestral proportions among the UM patients. Greater than 500,000 SNPs were phased and local ancestral calls were calculated on each patient. The genetic structure of individual patient samples revealed a diverse ancestral admixture among self-reported Hispanic patients with UM. Significant differences in global European ancestry were shown between Class 1A and Class 1B patients, where Class 1B patients were more European (P = 0.0087). Kruskal-Wallis test showed a significant difference between the three groups' european ancestry showing that Class 1A, Class 1B, and Class 2 distributions are not all the same (P=0.035). Patients with higher European ancestry are also more likely to be PRAME-positive (P=0.02). For local ancestry analysis, a linear regression was performed at each haplotype. A significance threshold of 0.000694 was established after correction for the mean number of ancestral switches in the cohort. Two regions on chr20 reached genome wide significance (P&lt;0.0006) with an enrichment of European ancestry in more aggressive malignancies. These findings present an exciting opportunity for studying ancestral genetic determinants on patient outcome in UM. The results show that genetic ancestry may influence the occurrence and clinical significance of prognostic biomarkers and patient outcomes in UM. Utilizing genetic ancestry may aid in our understanding and guide future management of ocular pathologies in admixed individuals.

Citation Format: Daniel Alexander Rodriguez, Margaret I. Sanchez, Christina L. Decatur, J. William Harbour. Quantitative ancestry analysis in Hispanic uveal melanoma patients reveals novel disease susceptibility loci [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1212.