Abstract 3396: Genomic landscape and ancestry-associated variations of gynecological cancers
Authors: Vasily N. Aushev, Carly B. Scalise, Rebecca C. Arend, Avinash Ramu, J. Bryce Ortiz, Alyssa Antonopoulos, Faraz Salmasi, Alexey Aleshin, Adam C. ElNaggar, Laura Chambers
Journal: Cancer Research (2025)

Abstract Background: Gynecological cancers are a diverse set of malignancies, each with distinct genomic alterations that influence tumorigenesis and disease progression. Here, we analyzed genomic data from endometrial, ovarian, and cervical cancer patients, stratified by genetic ancestry, to assess differences in genomic mutational landscapes. Methods: Whole-exome sequencing (WES) data from &amp;gt;8, 000 gynecological cancer cases in Natera’s proprietary Real-World Database were utilized. WES was performed on tumor tissues for designing personalized Signatera™ circulating tumor DNA tests ordered from June 2019 - November 2024. After exclusions, 6, 485 patients remained: 2, 956 (46%) endometrial, 2, 709 (42%) ovarian, and 820 (12%) cervical cancer. Variant calling used Mutect2 and VarScan2; only non-synonymous mutations were included in prevalence analysis. Genetic ancestry was determined using EthSeq algorithm for four groups: Africa (AFR), East Asia (EAS), Europe (EUR), South Asia (SAS). Results: In endometrial cancer, top mutated genes were PTEN (43.2%), ARID1A (37.9%), and PIK3CA (34.5%). The most common variants being SETD1B H8X (7.6%), RNF43 G659X (6.8%), PTEN R130G (5.8%) and PIK3CA H1047R (5.8%). EUR and AFR ancestry comprised 85% and 14% of cases, respectively. The top 4 most frequently mutated genes were the same in EUR and AFR; but EUR ancestry had significantly higher ARID1A (40.7% vs 23.6%, p&amp;lt;0.01), PIK3CA (36.1% vs 23.8%, p&amp;lt;0.05), and PTEN (46.8% vs 22.5% p&amp;lt;0.001) mutations, while AFR ancestry had higher prevalence of TP53 (51.2% vs 30.5%, p&amp;lt;0.01). In ovarian cancer, TP53 (53.3%), ARID1A (10.4%), and PIK3CA (9.7%) were the top mutated genes. Common variants were KRAS G12D and G12V (each 2.9%), and PIK3CA H1047R (2.5%). EUR and AFR groups comprised 79% and 8% of cases, respectively. No significant ancestry-based differences were found. In cervical cancer, PIK3CA (26.7%), KMT2C (14.0%), and KMT2D (11.5%) were most commonly mutated. The most common variants were PIK3CA E545K (13.0%), E542K (7.1%), and E726K (2.7%). EUR and AFR comprised 75% and 13% of cases, respectively, and harbored the same top two mutated genes: PIK3CA and KMT2C. The AFR group had a lower prevalence of PIK3CA E545K mutation (7.6% vs 14.4%) but a higher E542K prevalence (10.5% vs 6.8%). Conclusions: This extensive real-world genomic analyses of gynecological cancers revealed distinct mutational landscapes that distinguish ovarian, endometrial, and cervical cancers. The data highlight the genomic diversity of these malignancies and frequent alterations in genes and variants across ancestries, offering potential research targets. Future studies will investigate links between genomic alterations and clinical outcomes to inform disease management. Citation Format: Vasily N. Aushev, Carly B. Scalise, Rebecca C. Arend, Avinash Ramu, J. Bryce Ortiz, Alyssa Antonopoulos, Faraz Salmasi, Alexey Aleshin, Adam C. ElNaggar, Laura Chambers. Genomic landscape and ancestry-associated variations of gynecological cancers [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 3396.