Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers
Boruah, N.; Hoyos, D.; Moses, R.; Hausler, R.; Desai, H.; Le, A. N.; Good, M.; Kelly, G.; Raghavakaimal, A.; Tayeb, M.; Narasimhamurthy, M.; Doucette, A.; Gabriel, P.; Feldman, M. J.; Park, J.; Lopez de Rodas Gregorio, M.; Schalper, K. A.; Goldfarb, S. B.; Nayak, A.; Levine, A. J.; Greenbaum, B. D.; Maxwell, K. N.
Show abstract
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.
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