Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53

Abstract

Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li–Fraumeni syndrome concept to a wider cancer predisposition syndrome designated as the Li–Fraumeni spectrum. Here, we present a case with a malignant, metastatic perivascular epithelioid cell tumor (PEComa) of the thigh muscle and a sinonasal carcinoma harboring a novel TP53 germline splice mutation (NM_000546.5:c.97-2A>C). The classical presentation of LFS in the long-since deceased mother and the presence of a germline TP53 variant in the proband suggested a possible familial TP53-related condition. Complex pathological, molecular, and clinical genetic analyses (whole exome sequencing of germline variants, multigene panel sequencing of tumor DNA, Sanger validation, an in vitro functional test on splicing effect, 3D protein modeling, p53 immunohistochemistry, and pedigree analysis) were performed. The in vitro characterization of the splice mutation supported the pathogenic effect that resulted in exon skipping. A locus-specific loss of heterozygosity in the PEComa but not in the sinonasal carcinoma was identified, suggesting the causative role of the splice mutation in the PEComa pathogenesis, because we excluded known pathogenetic pathways characteristic to PEComas (TSC1/2, TFE3, RAD51B). However, the second hit affecting TP53 in the molecular pathogenesis of the sinonasal carcinoma was not identified. Although PEComa has been reported previously in two patients with Li–Fraumeni syndrome, to the best of our knowledge, this is the first report suggesting a relationship between the aberrant TP53 variant and PEComa.

Malignant perivascular epithelioid cell tumor (pecoma) of the uterus as part of the hereditary cancer syndrome: a case diagnosed with multiple malignancies

“…Galera López et al reported a simultaneous diagnosis of PEComa of the liver in two siblings with an LFS ( 23 ). Butz et al reported a malignant, metastatic PEComa of the thigh muscle harboring a novel TP53 germline splice mutation in an attenuated LFS patient ( 24 ). Our case is the first uterine PEComa with related LFS.…”

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

“…Bidirectional Sanger sequencing of the coding exons and exon-intron boundaries of the APC gene and multiplex ligation-dependent probe amplification (MLPA) testing for copy number variants by P043-E1 kit (MRC-Holland, The Netherlands) were performed. Whole exome sequencing was done as previously described [6,7] (see Supplementary Methods). Whole genome sequencing (WGS) was designed as a duo of the disease-affected proband and his nonaffected brother (details in Supplementary Methods).…”

Comprehensive Insights Into Renal Perivascular Epithelioid Cell Neoplasms: From Molecular Mechanisms to Clinical Practice

“…Research into most PEComas instances has revealed that mutations in TP53 often occur alongside alterations in TSC1/TSC2, TFE3, and other genes involved in PEComa development, with these gene mutations not being the sole cause of PEComas [24][25][26]. Recent research has pinpointed PEComas with TP53 mutations, absent of simultaneous TSC mutations or TFE3 rearrangements [27], indicating TP53's possible role as a key influencer in PEComa's emergence. Nonetheless, additional studies are required to de-termine if mutations in TP53 solely serve as the fundamental cause of PEComas without TSC mutations or TFE3 rearrangements [28,29].…”