Abstract 5469: Characterization of CCNE1 amplifications and associated genomic features in ovarian and uterine cancers
Authors: Sethuraman Sunantha , Glodzik Dominik , Selenica Pier , Johnson Adrienne , Reis-Filho Jorge S. , Veloso Artur , Silverman Ian M. 
Published: June 2023

Abstract
Amplification of the Cyclin E1 gene (CCNE1) is a recurrent genetic alteration in ovarian and uterine cancers. Therapeutic approaches to target cancers harboring CCNE1 amplification are being developed (e.g. PKMYT1, WEE1, and CDK2 inhibitors). In this study, we report the genomic landscape and architecture of CCNE1 amplifications using a combination of whole-exome (WES) and whole-genome sequencing (WGS) approaches. WES data from 361 ovarian and 580 uterine cancers was retrieved from TCGA. WGS data from 113 ovarian and 51 uterine cancers was retrieved from PCAWG. For both WES and WGS, amplification was defined as CN minus ploidy (CN-ploidy) &gt;= 4. CCNE1 amplification was detected in up to 21.2% of ovarian and 13.7% of uterine cancers from both methods. A review of the co-alteration landscape using WES revealed that TP53 alterations frequently co-occurred with CCNE1 amplifications in both ovarian and uterine cancers (ovarian: 95.8% vs 87.6%, OR = 3.24, p=0.1; uterine: 89.6% vs 36.0%, OR = 15.2, p =2.14e-13) and BRCA1 alterations were mutually exclusive with CCNE1 amplifications in ovarian cancer (2.1% vs 17.9%, OR=0.2, p = 3.1e-3). In addition, alterations in ARID1A (0% vs 40.5%, OR = 0, p = 1.3e-10) and PTEN (4.2% vs 60.1%, OR = 0.03, p =2.7e-15) were mutually exclusive with CCNE1 amplifications in uterine cancer. The number of CCNE1 copies ranged widely, with median CN-ploidy values of 9.3 (range: 4.0 -35.0) in ovarian and 7.7 (range: 4.0 -40.3) in uterine cancers from the WES cohort, and 7.4 (range: 4.1 -34.3) in ovarian and 11.0 (range: 4.6 - 81.9) in uterine cancers from WGS. We also observed a broad range of CCNE1 amplicon sizes, from highly focal to chromosome arm-level amplifications. WGS data showed frequent loss of heterozygosity (LOH) of chromosome 19 arms and an enrichment of fold-back inversions proximal to the CCNE1 amplicon implicating breakage-fusion-bridge in formation of CCNE1 amplicons. Whole genome duplication (WGD) was detected significantly more frequently in ovarian and uterine cancers with CCNE1 amplification than the wild-type group (ovarian: 90.9% vs 48.3%, p = 6.4e-10; uterine: 78.7% vs 21.9%, p = 7.1e-15). As compared to CCNE1 wild-type cancers, CCNE1-amplified cancers were found to display an enrichment for certain structural variant signatures: RS1, dominated by 100Kb-1Mb duplications (median = 30, p=0.08); RS2, dominated by translocations (median = 16, p=0.001); and RS7, dominated by 100Kb-1Mb deletions (median=23, p=0.0002). In conclusion, CCNE1-amplified ovarian and uterine cancers are enriched for TP53 alterations and display a high degree of genome instability manifested as WGD and characteristic structural variants. Fold-back inversions and LOH were frequently observed at the CCNE1 locus in tumors with CCNE1 amplification, suggesting a potential breakage-fusion-bridge mechanism in the genesis of this amplicon.
Citation Format: Sunantha Sethuraman, Dominik Glodzik, Pier Selenica, Adrienne Johnson, Jorge S. Reis-Filho, Artur Veloso, Ian M. Silverman. Characterization of CCNE1 amplifications and associated genomic features in ovarian and uterine cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5469.