Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

Musa Alharbi,Amal Almutairi,Alicia Y Zhou,Latifa Almubarak,Nada Altassan,Rasha Aljelaify,Cynthia L Neben,Nahla Mubarak,Fatimah Alqubaishi,Mariam Alsaeed,Weal Aljabarat,Malak Abedalthagafi,Lamia Al-Subaie

doi:10.1038/s41525-018-0074-3

Abstract

Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband’s father is homozygous for TP53 c.799C > T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

Highlights

Li-Fraumeni syndrome (LFS [MIM: 151623]) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors presenting in childhood, adolescence, and adulthood
The only genetic variations definitively associated with LFS are pathogenic variants in TP53, a tumor suppressor gene whose protein product mediates DNA damage response, apoptosis, and cell cycle arrest
Because choroid plexus carcinoma (CPC) is frequently found in families with LFS,[9] our initial pathology review included immunohistochemistry staining for p53

Summary

INTRODUCTION

Li-Fraumeni syndrome (LFS [MIM: 151623]) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors presenting in childhood, adolescence, and adulthood. The revised Chompret criteria was proposed to identify families with LFS beyond a strict clinical diagnosis by (1) increasing the minimum age of tumor onset and (2) identifying a unique subset of cancers ( CPC and ACC) for which genetic testing should be considered, regardless of family history.[2,3] The only genetic variations definitively associated with LFS are pathogenic variants in TP53 We add to the heterogeneity of LFS by reporting a rare TP53 missense variant, c.799C > T (p.Arg267Trp), in seven individuals from one non-consanguineous family from Saudi Arabia This family meets the revised Chompret criteria for a clinical diagnosis of LFS2,3 with a history of brain tumors including CPC, colorectal cancer, and liver cancer. While TP53 loss of heterozygosity is frequently observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare

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