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Related Experiment Video

Updated: Sep 1, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Ordered and deterministic cancer genome evolution after p53 loss.

Timour Baslan¹, John P Morris^1,2,3, Zhen Zhao^1,4

¹Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

|August 17, 2022

Summary

Loss of the tumor suppressor p53, crucial for genome stability, surprisingly follows a predictable evolutionary path during pancreatic cancer development. This discovery offers new therapeutic targets for TP53-mutant cancers.

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Area of Science:

Oncology
Genetics
Genomics

Background:

p53 inactivation is a common event in human cancers, promoting genomic instability.
The precise genome evolution patterns following p53 loss in tumorigenesis are poorly understood.

Purpose of the Study:

To investigate the genome evolution patterns after p53 inactivation in pancreatic ductal adenocarcinoma.
To determine if p53 loss leads to predictable or chaotic genome changes during cancer development.

Main Methods:

Utilized a mouse model of pancreatic ductal adenocarcinoma with early p53 loss of heterozygosity.
Employed single-cell sequencing and in situ genotyping to track genome evolution from p53 inactivation to cancer.
Analyzed histological stages alongside genomic changes throughout premalignant and malignant progression.

Main Results:

p53 inactivation in pancreatic cancer progression follows a deterministic four-phase genome evolution: loss of heterozygosity, deletions, genome doubling, and gains/amplifications.
Deletion events target specific pathways and become fixed, despite overall genomic heterogeneity.
Each phase of genome evolution correlates with distinct histological stages.

Conclusions:

p53 inactivation is not solely a gateway to genetic chaos but can drive predictable genome evolution patterns.
Understanding these deterministic patterns may reveal novel therapeutic strategies for TP53-mutant cancers.