Distinct genomic remodeling in Li Fraumeni Syndrome breast cancer

Background: Pathogenic germline variants (PGVs) in TP53 cause Li-Fraumeni Syndrome (LFS), a hereditary multicancer predisposition syndrome. Among females with LFS, breast cancer (BC) is the most prevalent malignancy, affecting 80-90% of carriers, typically at a much earlier age than sporadic cases and frequently exhibiting HER2 positivity. Interestingly, LFS-BC displays a high burden of short- amplified segments of aneuploidy (SAAS), suggesting that germline TP53 loss may drive tumorigenesis through distinct genomic mechanisms that remain poorly understood. Methods: To elucidate genotype-phenotype correlations underlying these unique genomic features, we performed whole-genome sequencing (WGS) and targeted sequencing on invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), and matched adjacent and contralateral normal breast tissues from individuals with LFS. Data were compared to early-onset nonLFS-BC and to The Cancer Genome Atlas (TCGA) tumors harboring either wild-type or somatic TP53 mutations. Results: Across hormone receptor (HR) subtypes, expected increases in genomic instability were observed in triple-negative versus ER+ nonLFS-BC. However, overall instability measures were similar or lower in LFS-BC. Specifically, in ER+ tumors, microsatellite instability (MSI) and aneuploidy scores were significantly lower in LFS-BC compared to nonLFS-BC. In contrast, LFS-BC exhibited a notable increase in segmental allelic imbalance (AI) with high-level amplifications-particularly within HER2+ subtypes. These amplified regions were significantly shorter than those in nonLFS-BC and often encompassed oncogenes such as ERBB2 , defining a distinct SAAS phenotype. Unlike sporadic TP53 -mutant breast cancers in TCGA, which showed globally elevated aneuploidy and HRD, LFS-BC uniquely accumulated focal, short amplifications. WGS of LFS DCIS and invasive tumors revealed predominant chromosomal instability (CN9) and chromothripsis (CN5) copy number signatures, with minimal whole-genome doubling. Amplicon Architect analysis identified ecDNA structures in 14 of 19 tumors, including ERBB2 -containing ecDNA in 3/6 DCIS and 5/9 HER2+ IDCs with 4 and 8 number of ecDNA structure in each category respevtively. Our work is consistent with prior reports of ecDNA in ~23% of breast cancers and up to 46% of HER2+ cases. Conclusion: LFS-associated breast cancers are defined by a unique genomic remodeling pattern characterized by focal, high-level amplifications within short aneuploid amplified segments (SAAS) and frequent ecDNA formation. These features distinguish LFS-BC from sporadic TP53 -mutant tumors and highlight a germline TP53 -driven mechanism of oncogene amplification and structural genome evolution.