Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers
Nearly all Li‑Fraumeni syndrome breast cancers exhibit biallelic loss of TP53 and lack recurrent oncogenic variants except ERBB2 (HER2) amplification
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.
Li‑Fraumeni syndrome‑associated breast cancers arise at a much younger age and display distinct genomic and immune characteristics, underscoring the need for focused surveillance and individualized therapeutic approaches.
Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.
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