Abstract C099: Genetic ancestry specific loss of heterozygosity of essential genes as therapeutic vulnerabilities in cancer

Abstract

Abstract Barriers in access to clinical care among under-served populations in combination with a vast underrepresentation at a scientific research level perpetuate inequalities in cancer treatment. These disparities are further disseminated due to the lack of understanding underlying genomic differences contributing to cancer outcome among these patients. The contributions of germline and somatic variations in cancer often shape treatment regimens, and these variations are not well investigated in non-European populations. We have described a class of potential therapeutic targets (GEMINI genes) that reflect a combination of germline alterations with somatic loss of heterozygosity (LOH). GEMINI genes are essential genes with frequent germline polymorphisms, whose frequency varies by ancestry. Indeed, because genomes of African ancestry tend to be the most diverse, many GEMINI genes are the most polymorphic in this patient population. When normal cells are heterozygous, LOH leaves cancer cells reliant on the gene products encoded by a single allele, where as healthy cells retain both copies. LOH is a common genetic event, often affecting over 20% of the genome in certain cancers, making this approach widely useful. Targeting GEMINI vulnerabilities opens up possibilities for allele-specific inhibitors or degrader therapeutics that can be catered in an ancestry-dependent manner, to ameliorate inequities in cancer genomics research. One approach to readily target individual alleles is to utilize nucleic acid-based methods, as we’ve previously demonstrated using PRIM1. This therapeutic is expected to be the most specific when targeting polymorphisms that create the greatest differences between alleles. Here, we have prioritized a set of GEMINI targets based upon the extent of differences between alleles, and rates of heterozygosity and LOH across populations. Our initial analysis of TCGA data identified 5664 variants in 1278 essential genes that undergo LOH in cancer. We filtered GEMINI vulnerabilities by means of insertion-deletion (indel) difference of the alternate allele compared to the reference allele, followed by sorting based off maximum allele frequency by genetic ancestry. Here, we identify 31 variants across 23 genes enriched in African ancestry, 7 variants across 7 genes enriched in American ancestry, 12 variants across 12 genes enriched in East Asian ancestry, 4 variants enriched in 4 genes in South Asian ancestry, and 3 variants enriched in 3 genes in European ancestry. In addition, each of these ancestry-specific GEMINI genes exhibit a minimum 10% pan-cancer LOH rate, with the highest LOH frequencies observed in ovarian and kidney chromophobe cancers. As both these cancers exhibit disparities in mortality at a population level, targeting GEMINI genes as a therapeutic strategy may aid in lessening the disproportionate rate of outcome resultant of these cancers. Overall, we identify novel GEMINI genes to assess ancestry-specific genomic variations to serve as targets for precision treatment specific to underserved patient populations. Citation Format: Nicole Peiris, Catherine Hazard, Charlotte E. Farquhar, Andrei Loas, Bradley L. Pentelute, Rameen Beroukhim. Genetic ancestry specific loss of heterozygosity of essential genes as therapeutic vulnerabilities in cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C099.