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<p>Li–Fraumeni syndrome (LFS) is a hereditary cancer-predisposing disorder caused by germline pathogenic variants in the <i>TP</i>53 gene. Attenuated LFS represents a clinically milder form characterized by lower penetrance and later tumor onset, evading standard diagnostic criteria. We report a case of a 36-year-old Japanese woman who presented with hematochezia and was diagnosed with metastatic rectal adenocarcinoma. After failure of the first- to third-line chemotherapies, plasma-based comprehensive genomic profiling (CGP) was performed. The assay revealed a <i>TP</i>53 p.R181H variant (allele frequency: 0.512), <i>KRAS</i> p.G12D variant, <i>PIK3CA</i> p.E545K variant, and a <i>CTNNB1</i> splicing variant. Family history included multiple gastrointestinal and hematological malignancies in first- and second-degree relatives. Germline testing confirmed heterozygosity of <i>TP</i>53 p.R181H, a temperature-sensitive variant suggested to have reduced penetrance. Notably, this variant is relatively common in European populations but rare in East Asian cohorts. To the best of our knowledge, this is the first reported East Asian case of attenuated LFS associated with the <i>TP</i>53 p.R181H variant. This case underscores the broader phenotypic spectrum of LFS. With the growing use of CGP, LFS may be identified more frequently in East Asia, potentially revealing attenuated LFS missed by traditional diagnostic criteria.</p>

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Attenuated Li–Fraumeni syndrome with TP53 p.R181H in a Japanese patient with metastatic rectal adenocarcinoma: a case report

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Yuki Kasahara,
  • Masanobu Takahashi,
  • Yoshifumi Kawamura,
  • Yoko Aoki,
  • Tetsuya Niihori,
  • Maako Kawamura,
  • Shinnosuke Yamamoto,
  • Hidekazu Shirota,
  • Ken Saijo,
  • Hiroo Imai,
  • Keigo Komine,
  • Kota Ouchi,
  • Sakura Taniguchi,
  • Yuya Yoshida,
  • Ryunosuke Numakura,
  • Shiori Ishikawa,
  • Tomoaki Shirakawa,
  • Ryo Saito,
  • Chikashi Ishioka,
  • Hisato Kawakami

摘要

Li–Fraumeni syndrome (LFS) is a hereditary cancer-predisposing disorder caused by germline pathogenic variants in the TP53 gene. Attenuated LFS represents a clinically milder form characterized by lower penetrance and later tumor onset, evading standard diagnostic criteria. We report a case of a 36-year-old Japanese woman who presented with hematochezia and was diagnosed with metastatic rectal adenocarcinoma. After failure of the first- to third-line chemotherapies, plasma-based comprehensive genomic profiling (CGP) was performed. The assay revealed a TP53 p.R181H variant (allele frequency: 0.512), KRAS p.G12D variant, PIK3CA p.E545K variant, and a CTNNB1 splicing variant. Family history included multiple gastrointestinal and hematological malignancies in first- and second-degree relatives. Germline testing confirmed heterozygosity of TP53 p.R181H, a temperature-sensitive variant suggested to have reduced penetrance. Notably, this variant is relatively common in European populations but rare in East Asian cohorts. To the best of our knowledge, this is the first reported East Asian case of attenuated LFS associated with the TP53 p.R181H variant. This case underscores the broader phenotypic spectrum of LFS. With the growing use of CGP, LFS may be identified more frequently in East Asia, potentially revealing attenuated LFS missed by traditional diagnostic criteria.