Abstract 5031: Analyzing <i>CHEK2</i>’s role in breast cancer via <i>CHEK2</i>-specific genomic profiles

Abstract Background: CHEK2 is a tumor suppressor gene in multiple types of cancers, notably estrogen receptor-positive (ER+) breast cancer (BC). We previously revealed that CHEK2-derived BC genomes have specific genomic features that are dissimilar from BRCA1/2-initiated BC genomes suggesting a different underlying biology. In the study, we aimed to identify estrogen receptor-positive (ER+) samples that are wild-type for CHEK2 but which exhibit similar properties to CHEK2 mutated tumors to reveal additional genetic drivers of this phenotype. Methods: Using whole genome sequencing data of primary and metastatic BC from different subtypes, we categorized the size distribution of structural variants (SVs) such as inversions (INV), tandem duplications (DUP), and deletions (DEL) separately, and established CHEK2-specific SV profiles. We calculated cosine similarity (CS) scores for all samples comparing the SV profile of a sample to that of the baseline SV profile of CHEK2 samples. We labeled ER+ samples without CHEK2 mutation as ER+ CHEK2-like samples if their CS scores were higher than the average + 1 SD of the actual CHEK2 samples. We also studied the location of SVs, defined CHEK2-specific sizes of SVs, and investigated the genes with SVs of these sizes. Lastly, we compared germline mutation frequencies of ER+ CHEK2-like and ER+ CHEK2-unlike tumors. Results: The SV size distributions of 926 primary BCs were established for INV, DUP, and DELs. The INV SV profile of CHEK2 tumors proved very similar in all ER+ tumors and was not used in the classification. Using the CS scores of ER+ tumors to the CHEK2-specific DUP and DEL size distributions, 31 and 47 samples, respectively, were classified as ER+ CHEK2-like tumors. Interestingly, DUPs in CHEK2 and ER+ CHEK2-like tumors were localized, mainly on recurrently affected chromosomes 11 and 17 for ER+ BC. However, no regions or genes specific for CHEK2 tumors were observed in the ER+ CHEK2-like tumors compared to ER+ CHEK2-unlike tumors. Evaluating germline genetic variations in ER+ CHEK2-like and -unlike tumors, we found 7 genes, EBLN2, TAAR2, FAM166B, PNPLA7, IL1RAPL1, ABCC12, and SLC23A2, with increased mutation frequency in ER+ CHEK2-likes (p&amp;lt;0.05), but none of them remained significant after correction for multiple testing. Conclusion: Our method of selecting ER+ samples with similar SV profiles as CHEK2 tumors appeared successful and will likely facilitate the identification of potential CHEK2-associated pathways. Tandem duplications in CHEK2 and CHEK2-like cancers mapped to specific chromosomes but did not pin-point recurrent genes. Only four potential genes with increased germline mutation frequency in ER+ CHEK2-likes (TAAR2, PNPLA7, ABCC12, SLC23A2) have been associated in literature with BC or its subtypes, but none of them connected to CHEK2-related biology. Citation Format: Shuoying Qu, Marcel Smid, John Martens, Antoinette Hollestelle. Analyzing CHEK2’s role in breast cancer via CHEK2-specific genomic profiles [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 5031.