Data from Clinical and Functional Significance of TP53 Exon 4–Intron 4 Splice Junction Variants

Abstract

<div>Abstract<p>Germline <i>TP53</i> splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4–intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACT). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and <i>in silico</i> assays to determine protein stability, splicing, and transcriptional activity of 10 <i>TP53</i> variants at exon 4–intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of <i>TP53</i> variants in human cancer and examined individual reports, focusing on family history of cancer. <i>TP53</i> exon 4–intron 4 junction germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional eight independent <i>TP53</i> variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project (<i>n</i> = 5,213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization, and loss of function. Clinical case review of carriers of <i>TP53</i> exon 4–intron 4 junction variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni syndrome. Germline variants involving <i>TP53</i> exon 4–intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline <i>TP53</i> variants on the fidelity of splicing, protein structure, and function must be considered in evaluating cancer susceptibility.</p>Implications:<p>Taken together, the data indicate that splice variants at <i>TP53</i> codon 125 and surrounding bases differentially impacted p53 gene expression and function.</p></div>