Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models.

Chang S Chan,Wenwei Hu,Merzu Belete,Hua Ke,Zhaohui Feng,Yuhan Zhao,Cen Zhang,Arnold J Levine,Yvonne Sun

doi:10.26508/lsa.202000952

Abstract

p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying Tp53 mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.

Highlights

Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers (Olivier et al, 2002)
This study examined the impact of the genetic background of the F-1 Li-Fraumeni mouse model on tumor formation
In humans with Li-Fraumeni syndrome caused by an inherited Tp53 mutation, the Tp53 gene deficit can result in many diverse tumor types

Summary

Introduction

Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers (Olivier et al, 2002). One in 20,000 individuals inherit heterozygous p53 mutations, resulting in early onset and high frequency of cancers in each patient over a lifetime (Li & Fraumeni, 1969). Recent studies have suggested that inherited p53 mutations may occur at frequencies of 1/500 to 1/2,000 individuals in the general population without the early onset or high frequency of cancers (de Andrade et al, 2017, 2019). If this is correct, these data suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype (Shi et al, 2009; Chan, 2017)

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