Abstract 4849: Mosaic chromosomal alterations in a prospective cohort of Mexican Americans for cancer risk and genetic insights
Authors: Valdebenito Jessica , Wong Justin , Chang Dahwei , Gomez Henry , Nead Kevin T , Jakubek Yasminka , Scheet Paul 
Published: March 2024

Abstract
Introduction: In this study, we aim to explore mosaic chromosomal alterations (mCA) and their implications in cancer risk among Mexican Americans (MA) - an expanding yet historically underrepresented ethnic minority in the U.S. In addition, we propose to develop a novel method that identifies high mutant cell fraction (MCF) copy-neutral Loss of heterozygosity (cn-LOH). At sufficiently high MCF, these will look like runs of homozygosity (ROH) and may be missed by current mCA detection techniques that rely on identified germline heterozygote genotypes. Our preliminary findings revealed frequent and widespread homozygosity across the genome, predominantly in short regions (&lt;10 Mb), although some exceeded 100 Mb. Our objective is to advance mCA detection techniques, differentiating cn-LOH from ROH, to deepen our understanding of mCA.
Methods: We analyzed SNP array data from blood and saliva samples of 1657 individuals, focusing on cancer and chronic disease risk ages, from the Mano a Mano Mexican American Cohort Study. We applied hapLOH and MoChA, both haplotype-based methods, to detect mCA. To identify high-MCF cn-LOH, we first scanned for observed ROH using PLINK. Separately, we develop a statistical framework through simulations to differentiate high-MCF cn-LOH from ROH. We considered multiple methods; initially, we built a statistical framework using a hypothesis-testing approach (H0: ROH; H1: cn-LOH), where we compared the “B allele” frequency information within observed ROH. To split this information and obtain our groups, we used population genetic principles. Secondly, we classified our events, calculating the likelihood ratio of our statistical hypotheses. Finally, we explored a haplotype-based imputation approach that leverages flanking diploid region information.
Results: We identified numerous mCA, predominantly in individuals without cancer. Simulations showed effective classification in larger homozygosity regions (&gt;10 Mb), guiding our methodological focus on detecting shorter high-MCF regions. Not surprisingly, extremely high MCFs (0.99-1) presented challenges in accurate identification.
Conclusion and Future Directions: To improve our mCA results description, we will thoroughly characterize and study their association with cancer phenotypes and environmental exposures. We are in the process of genotyping the entire cohort, which consists of over 25,000 participants. To date, our cohort includes 909 cancer cases, of which 262 are hematological malignancies. We sought to design a unique method that differentiates high-MCF cn-LOH from observed ROH, improving current mCA discovery. Our focus is on small regions as they provide limited information to infer event types. Our next step is to characterize and validate our results, especially in pathologically normal samples, as a way of identifying potential biomarkers of interest.
Citation Format: Jessica Valdebenito, Justin Wong, Dahwei Chang, Henry Gomez, Kevin T Nead, Yasminka Jakubek, Paul Scheet. Mosaic chromosomal alterations in a prospective cohort of Mexican Americans for cancer risk and genetic insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4849.