Abstract 2403: Efficient detection of whole genome duplication: a targeted sequencing approach

Objective: Whole Genome Duplication (WGD) involves the replication of an organism's entire genome and is linked to increased evolutionary complexity and cancer progression. In tumors, WGD contributes to heterogeneity and therapy resistance, making its identification crucial for targeting genomic instabilities and informing treatment strategies. Current methods for detecting WGD are often expensive and time-consuming, highlighting the need for a cost-effective and efficient detection panel to improve therapeutic strategies, patient outcomes, and resource allocation in clinical settings. Methods: We retrospectively analyzed 4,941 tissue samples from patients spanning 14 different cancer types, including ovarian, uterine, breast, pancreatic, prostate, cervical, liver, lung, colorectal, and gastric cancers. Using a targeted sequencing panel (GENESEEQ GENAVISTA) focused on 437 cancer-related genes, we performed comprehensive mutational profiling (∼1,000X). WGD was determined by analyzing read depth, allele frequency, and employing variant calling algorithms to detect gene duplications and genomic rearrangements. Additionally, a prospective cohort of 33 cancer patients was evaluated to compare the performance of our panel with whole exome sequencing (WES, ∼200X) and whole genome sequencing (WGS, ∼30X). Results: Our analysis revealed varying prevalence of WGD across cancer types, with significant rates observed in ovarian (50.93%) and breast cancers (52.32%). Pelvic cancer (60.61%) and melanoma (60.00%) also showed high WGD-positive rates. Conversely, endometrial cancer exhibited a notably lower rate of 19.41%. Pancreatic and prostate cancers showed moderate WGD frequencies of 27.46% and 21.51%, respectively, while liver and bile duct cancers had an incidence of 41.30%. In the prospective cohort, our panel demonstrated higher sensitivity compared to WES (100% vs. 84.62%) but slightly lower specificity (90% vs. 95%). The overall concordance with the gold standard WGS was 93.9%, surpassing that of WES (90.9%). Conclusion: Our study highlights the significant variability of WGD across cancer types, with a notably high prevalence in ovarian and breast cancers. This underscores the potential of WGD as a biomarker for therapeutic targeting. Our targeted sequencing panel offers an efficient and cost-effective detection method, demonstrating substantial clinical potential for informing personalized treatment strategies and improving patient outcomes. Citation Format: Hua Bao, Haimeng Tang, Rui Liu, Ningyou Li, Min Wu, Xunbiao Liu, Zhili Chang, Xue Wu. Efficient detection of whole genome duplication: a targeted sequencing approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2403.