Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer.

Yaxuan Liu,Tom Van Leeuwen,Pedram Kharaziha,Svetlana Bajalica-Lagercrantz,Catharina Larsson,Robert Konrat,Olga Axell,Anthony P H Wright

doi:10.3390/ijms22126345

Abstract

Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78−0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.

Highlights

Li-Fraumeni syndrome (LFS) is a rare heritable extreme tumor risk syndrome characterized mainly by premenopausal breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma and adrenocortical carcinoma, and was first described in 1969 [1]
A total of 48 germline TP53 missense variants were selected from the IARC database, Fortuno et al [24] and Kharaziha et al [25] including 24 uniquely observed in LFS and 24 exclusively reported in hereditary breast cancer (HBC) (Figure S1)
23 variants in the LFS-group were located in the DNA binding domain (DBD) and one in the oligomerization domain

Summary

Introduction

Li-Fraumeni syndrome (LFS) is a rare heritable extreme tumor risk syndrome characterized mainly by premenopausal breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma and adrenocortical carcinoma, and was first described in 1969 [1]. As more families with a variety of tumors were reported, less restricted criteria became used to define Li-Fraumeni-like (LFL) families [3] that did not meet the classical LFS criteria but were suggestive of LFS, with a detection rate for germline TP53 alterations of 20–40% in LFL as compared to 70% in LFS [4]. The most commonly used screening criteria are the Chompret criteria, with a detection rate of 29%, since they include a large group of patients for screening [5]. According to these criteria a patient with breast cancer below 31 years, should be screened irrespective of family history. With the increased use of cancer gene panels in genetic testing, the detection of pathogenic TP53 variants has increased, and up to 1% of families with exclusively hereditary breast cancer (HBC) have been shown to carry a germline TP53 variant [6]

Methods

Results

Conclusion