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 Interests: 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.