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

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.

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Publication Details

Journal
Nature Communications
Published
2026-05-21
DOI
https://doi.org/10.1038/s41467-026-73163-4
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

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

M FELDMAN, Ashvathi Raghavakaimal, Benjamin D. Greenbaum, Mohana Narasimhamurthy et al.
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Cancer-related Molecular Pathways
article

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

M FELDMAN, Ashvathi Raghavakaimal, Benjamin D. Greenbaum, Mohana Narasimhamurthy, Peter Gabriel, Anupma Nayak, Nabamita Boruah, Jinae Park, Renyta Moses, Maliha Tayeb, Heena Desai, AJ Levine, A Dinh Le, K. N. Maxwell, Gregory Kelly, Ryan Hausler, Kurt A. Schalper, Madeline Good, Abigail Doucette, David Hoyos, Miguel Lopez de Rodas, Shari B. Goldfarb
article en

Abstract

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.

Nature Communications
Memorial Sloan Kettering Cancer Center (US), Cornell University (US), Yale University (US), Institute for Advanced Study (US), Philadelphia VA Medical Center (US), University of Pennsylvania (US)
Burroughs Wellcome Fund, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 7%
Cancer-related Molecular Pathways
DOIOpen Access PDFOpenAlex
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