Abstract 3018: Transcriptional dysregulation in germline TP53-driven breast cancers
Authors: Boruah Nabamita , Moses Renyta , Hausler Ryan , Desai Heena , Le Anh , Kelly Gregory , Raghavakaimal Ashvathi , Narasimhamurthy Mohana , Nayak Anupma , Levine Arnold J. , Maxwell Kara N. 
Published: March 2024

Abstract
Background: Pathogenic germline variants (PGVs) in TP53 is associated with multicancer risk syndrome known as Li-Fraumeni Syndrome (LFS) and females have 80-90% risk of breast cancer at very early age compared to sporadic breast cancers. The mechanism of p53 tumor suppression relies on its function as a transcriptional activator; however, there is little data on the specific transcriptional defects in human breast tumors driven by germline mutant p53.
Methods: To investigate the specific transcriptional defects due to TP53 PGVs in human breast, we performed bulk RNA-seq on invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS) and surrounding and contralateral normal breast tissue in LFSBC compared to non-LFS sporadic BC. We also compared our results to breast tumors from The Cancer Genome Atlas (TCGA) with and without acquired TP53 mutations.
Results: Our RNA-seq analysis revealed significant changes in the expression of key pathways in LFSBC compared to non-LFS breast cancer. Notably, cancer hallmark pathways such as apoptosis and reactive oxygen species were downregulated, while androgen response and cholesterol homeostasis pathways were upregulated in LFSBC compared to non-LFSBC. Expression of downstream targets of p53 such as BAX, tumor suppressors such as CDKN1A (p21) and BTG2, were significantly down in LFSBC suggesting impaired transcriptional activity of mutated TP53 in LFS patients. We also observed downregulation of cell cycle regulators in LFS breast tumors compared to their surrounding and contralateral tissues. Although, there were no significant transcriptional differences as the tumor progressed from LFS DCIS to IDC, indicating that the damage caused by the mutated p53 had already occurred at the early stage. Additionally, we also investigated the immune cell composition in LFS-BC and non-LFSBC. LFSBC exhibited a higher relative proportion of CD4+ T cells, CD20+ B cells, NK cells, macrophages and monocytes compared to all sporadic non-LFSBC subtypes (TCGA) and age matched non-LFSBC. This providing novel insights into the immune landscape associated with LFS-driven breast cancer.
Conclusion: Our findings suggest that breast tissues with an inherited TP53 mutation undergo a defective transcriptional state, shifting away from apoptosis, and experiencing dysregulation of cell cycle at an early stage as DCIS, potentially contributing to the early onset of LFS breast cancer. The preliminary analysis of immune repertoire in LFSBC opens avenues for deeper investigations into spatial transcriptomic profiles of germline TP53-mutated breast tumors also the immune cells. Overall, this study provides valuable insights into the TP53 mutation driven breast cancers in humans.
Citation Format: Nabamita Boruah, Renyta Moses, Ryan Hausler, Heena Desai, Anh Le, Gregory Kelly, Ashvathi Raghavakaimal, Mohana Narasimhamurthy, Anupma Nayak, Arnold J. Levine, Kara N. Maxwell. Transcriptional dysregulation in germline TP53-driven breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3018.