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.

doi:10.1101/2024.04.03.588009

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bioRxiv · 10.1101/2024.04.03.588009

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

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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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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.. 2024-04-07. Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers. https://doi.org/10.1101/2024.04.03.588009

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