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

Ori Hassin, Nishanth Belugali Nataraj, Michal Shreberk-Shaked, Yael Aylon, Rona Yaeger, Giulia Fontemaggi, Saptaparna Mukherjee, Martino Maddalena, Adi Avioz, Ortal Iancu, Giuseppe Mallel, Anat Gershoni, Inna Grosheva, Ester Feldmesser, Shifra Ben-Dor, Ofra Golani, Ayal Hendel, Giovanni Blandino, David Kelsen, Yosef Yarden and Moshe Oren ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30481-7

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