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<p>Pathogenic germline <i>TP53</i> 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 <i>TP53</i>, with no recurrent oncogenic variants except <i>ERBB2</i> (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 <i>BAX</i> and <i>TP53I3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月21日

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  • Nabamita Boruah,
  • David Hoyos,
  • Renyta Moses,
  • Ryan Hausler,
  • Heena Desai,
  • Anh N. Le,
  • Madeline Good,
  • Gregory Kelly,
  • Ashvathi Raghavakaimal,
  • Maliha Tayeb,
  • Mohana Narasimhamurthy,
  • Abigail Doucette,
  • Peter Gabriel,
  • Michael J. Feldman,
  • Jinae Park,
  • Miguel Lopez de Rodas,
  • Kurt A. Schalper,
  • Shari B. Goldfarb,
  • Anupma Nayak,
  • Arnold J. Levine,
  • Benjamin D. Greenbaum,
  • Kara N. Maxwell

摘要

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.