Number of rare germline CNVs and TP53 mutation types

Amanda G Silva,Maria Isabel Waddington Achatz,Peter L Pearson,Carla Rosenberg,Ana Cv Krepischi

doi:10.1186/1750-1172-7-101

Amanda G Silva, Maria Isabel Waddington Achatz + Show 3 more

Open Access

https://doi.org/10.1186/1750-1172-7-101

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Abstract

BackgroundThe Li-Fraumeni syndrome (LFS), an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families. Increases in copy number variation (CNV) have been reported in TP53 mutated individuals, and are also postulated to contribute to LFS phenotypic variability. The Brazilian p.R337H TP53 mutation has particular functional and regulatory properties that differ from most other common LFS TP53 mutations, by conferring a strikingly milder phenotype.MethodsWe compared the CNV profiles of controls, and LFS individuals carrying either p.R337H or DNA binding domain (DBD) TP53 mutations by high resolution array-CGH.ResultsAlthough we did not find any significant difference in the frequency of CNVs between LFS patients and controls, our data indicated an increased proportion of rare CNVs per genome in patients carrying DBD mutations compared to both controls (p=0.0002***) and p.R337H (0.0156*) mutants.ConclusionsThe larger accumulation of rare CNVs in DBD mutants may contribute to the reported anticipation and severity of the syndrome; likewise the fact that p.R337H individuals do not present the same magnitude of rare CNV accumulation may also explain the maintenance of this mutation at relatively high frequency in some populations.

Highlights

The Li-Fraumeni syndrome (LFS), an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families
LFS arises from germline mutations in the TP53 gene, which codes for a transcription factor implicated in cell proliferation, apoptosis, and genomic stability [3,4]
It has been more recently observed that individuals carrying TP53 mutations show a ~3-fold increase in DNA copy number variation (CNV) compared to controls, suggesting that CNVs make an additive contribution to cancer risk [13]

Summary

Introduction

The Li-Fraumeni syndrome (LFS), an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families. Increases in copy number variation (CNV) have been reported in TP53 mutated individuals, and are postulated to contribute to LFS phenotypic variability. Li-Fraumeni syndrome (LFS; OMIM #151623) is an autosomal dominant highly penetrant cancer predisposition syndrome characterized by a variety of early onset tumors [1,2]. It has been more recently observed that individuals carrying TP53 mutations show a ~3-fold increase in DNA copy number variation (CNV) compared to controls, suggesting that CNVs make an additive contribution to cancer risk [13]

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