Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers
- Nabamita Boruah
- David Hoyos
- Renyta Moses
- Ryan Hausler
- Heena Desai
- Anh N. Le
- Madeline Good
- Gregory Kelly
- Ashvathi Raghavakaimal
- Maliha Tayeb
- Mohana Narasimhamurthy
- Abigail Doucette
- Peter Gabriel
- Michael J. Feldman
- Jinae Park
- Miguel Lopez de Rodas
- Kurt A. Schalper
- Shari B. Goldfarb
- Anupma Nayak
- Arnold J. Levine
- Benjamin D. Greenbaum
- Kara N. Maxwell
2026-05-21
Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer (BC) is the most common cancer in LFS females. Here, we perform a multimodal analysis, comparing LFS-BC with sporadic premenopausal breast cancer which shows that nearly all LFS-BC undergo biallelic loss of TP53 , with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibit a high burden of short amplified aneuploid segments. Pro-apoptotic p53 target genes BAX and TP53I3 fail to be up-regulated in LFS-BC unlike in sporadic BC compared to normal breast tissue. LFS-BC has lower CD8 + T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC is marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.