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Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients

Author

Listed:
  • Ori Hassin

    (Weizmann Institute of Science)

  • Nishanth Belugali Nataraj

    (Weizmann Institute of Science)

  • Michal Shreberk-Shaked

    (Weizmann Institute of Science)

  • Yael Aylon

    (Weizmann Institute of Science)

  • Rona Yaeger

    (Memorial Sloan Kettering Cancer Center)

  • Giulia Fontemaggi

    (Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute)

  • Saptaparna Mukherjee

    (Weizmann Institute of Science)

  • Martino Maddalena

    (Weizmann Institute of Science)

  • Adi Avioz

    (Weizmann Institute of Science)

  • Ortal Iancu

    (Bar-Ilan University)

  • Giuseppe Mallel

    (Pathology Department, Curesponse Ltd)

  • Anat Gershoni

    (Weizmann Institute of Science)

  • Inna Grosheva

    (Weizmann Institute of Science)

  • Ester Feldmesser

    (Weizmann Institute of Science)

  • Shifra Ben-Dor

    (Weizmann Institute of Science)

  • Ofra Golani

    (Weizmann Institute of Science)

  • Ayal Hendel

    (Bar-Ilan University)

  • Giovanni Blandino

    (Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute)

  • David Kelsen

    (Memorial Sloan Kettering Cancer Center)

  • Yosef Yarden

    (Weizmann Institute of Science)

  • Moshe Oren

    (Weizmann Institute of Science)

Abstract

The TP53 gene is mutated in approximately 60% of all colorectal cancer (CRC) cases. Over 20% of all TP53-mutated CRC tumors carry missense mutations at position R175 or R273. Here we report that CRC tumors harboring R273 mutations are more prone to progress to metastatic disease, with decreased survival, than those with R175 mutations. We identify a distinct transcriptional signature orchestrated by p53R273H, implicating activation of oncogenic signaling pathways and predicting worse outcome. These features are shared also with the hotspot mutants p53R248Q and p53R248W. p53R273H selectively promotes rapid CRC cell spreading, migration, invasion and metastasis. The transcriptional output of p53R273H is associated with preferential binding to regulatory elements of R273 signature genes. Thus, different TP53 missense mutations contribute differently to cancer progression. Elucidation of the differential impact of distinct TP53 mutations on disease features may make TP53 mutational information more actionable, holding potential for better precision-based medicine.

Suggested Citation

  • Ori Hassin & Nishanth Belugali Nataraj & Michal Shreberk-Shaked & Yael Aylon & Rona Yaeger & Giulia Fontemaggi & Saptaparna Mukherjee & Martino Maddalena & Adi Avioz & Ortal Iancu & Giuseppe Mallel & , 2022. "Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30481-7
    DOI: 10.1038/s41467-022-30481-7
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    1. Juan Liu & Yiyun Shen & Jie Liu & Dandan Xu & Chun-Yuan Chang & Jianming Wang & Jason Zhou & Bruce G. Haffty & Lanjing Zhang & Jill Bargonetti & Subhajyoti De & Wenwei Hu & Zhaohui Feng, 2025. "Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation," Nature Communications, Nature, vol. 16(1), pages 1-18, December.

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