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; Moshe Oren

doi:10.1038/s41467-022-30481-7

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 YardenMoshe Oren

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English
Article number	2800
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30481-7
State	Published - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

We thank Benjamin Geiger for inspiring scientific discussions. We thank Carine Joubran for experimental help and Ron Rotkopf for statistical help. RNA-seq analysis was done with critical advice from Michal Pearl and Hadas Keren-Shaul of the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of science. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a Center of Excellence grant No. 3165/20 from the Israel Science Foundation, the Robert Bosch Stiftung and the Berthold Leibinger Stiftung, the Thompson Family Foundation, and a grant from Anat and Amnon Shashua, and the Moross Integrated Cancer Center. M.O. is incumbent of the Andre Lwoff chair in molecular biology. Cartoons in Figs. , , and were created with BioRender.com. We thank Benjamin Geiger for inspiring scientific discussions. We thank Carine Joubran for experimental help and Ron Rotkopf for statistical help. RNA-seq analysis was done with critical advice from Michal Pearl and Hadas Keren-Shaul of the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of science. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a Center of Excellence grant No. 3165/20 from the Israel Science Foundation, the Robert Bosch Stiftung and the Berthold Leibinger Stiftung, the Thompson Family Foundation, and a grant from Anat and Amnon Shashua, and the Moross Integrated Cancer Center. M.O. is incumbent of the Andre Lwoff chair in molecular biology. Cartoons in Figs. 2a , 3a , and 6a, b were created with BioRender.com.

Funders	Funder number
Anat and Amnon Shashua
Michal Pearl and Hadas Keren-Shaul of the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of science
Moross Integrated Cancer Center
National Cancer Institute	P30CA008748
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation	3165/20
Berthold Leibinger Stiftung
Thompson Family Foundation
Robert Bosch Stiftung
Israel Science Foundation

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Hassin, O., Nataraj, N. B., Shreberk-Shaked, M., Aylon, Y., Yaeger, R., Fontemaggi, G., Mukherjee, S., Maddalena, M., Avioz, A., Iancu, O., Mallel, G., Gershoni, A., Grosheva, I., Feldmesser, E., Ben-Dor, S., Golani, O., Hendel, A., Blandino, G., Kelsen, D., ... Oren, M. (2022). Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients. Nature Communications, 13(1), Article 2800. https://doi.org/10.1038/s41467-022-30481-7

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title = "Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients",

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.",

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

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Hassin, O, Nataraj, NB, Shreberk-Shaked, M, Aylon, Y, Yaeger, R, Fontemaggi, G, Mukherjee, S, Maddalena, M, Avioz, A, Iancu, O, Mallel, G, Gershoni, A, Grosheva, I, Feldmesser, E, Ben-Dor, S, Golani, O, Hendel, A, Blandino, G, Kelsen, D, Yarden, Y & Oren, M 2022, 'Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients', Nature Communications, vol. 13, no. 1, 2800. https://doi.org/10.1038/s41467-022-30481-7

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T1 - Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients

AU - Hassin, Ori

AU - Nataraj, Nishanth Belugali

AU - Shreberk-Shaked, Michal

AU - Aylon, Yael

AU - Yaeger, Rona

AU - Fontemaggi, Giulia

AU - Mukherjee, Saptaparna

AU - Maddalena, Martino

AU - Avioz, Adi

AU - Iancu, Ortal

AU - Mallel, Giuseppe

AU - Gershoni, Anat

AU - Grosheva, Inna

AU - Feldmesser, Ester

AU - Ben-Dor, Shifra

AU - Golani, Ofra

AU - Hendel, Ayal

AU - Blandino, Giovanni

AU - Kelsen, David

AU - Yarden, Yosef

AU - Oren, Moshe

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

UN SDGs

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