Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had 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 was 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. ### Competing Interest Statement NB, RM, RH, HD, AL, MG, GK, AR, MT, MLR and KNM report no conflicts of interest. KAS reports fees for consultant services, advisor or speaker from Clinica Alemana Santiago, Shattuck Labs, AstraZeneca, Takeda, Torque/Repertoire Therapeutics, CSRlife, Agenus, Genmab, Sanofi, Parthenon Therapeutics, Bristol-Myers Squibb, Roche, Molecular Templates, Merck, PeerView, PER and Forefront Collaborative. KAS reports research funding from Tesaro/GSK, Moderna Inc., Takeda, Surface Oncology, Merck, Bristol-Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer-Ingelheim, Roche and Akoya Biosciences. AJL is founder and shareholder of PMV Pharma, a biotech company that works on reactivator of mutant p53. B.G. has received honoraria for speaking engagements from Merck, Bristol Meyers Squibb, and Chugai Pharmaceuticals; has received research funding from Bristol Meyers Squibb and Merck; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, and ROME Therapeutics of which he is a co-founder.