Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome

Abstract

Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient’s blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mutation in the bilateral tumours might indicate the possibility of a postzygotic somatic mutation that along with the germline mutation of the same gene could represent an intriguing genetic phenomenon (type 2 segmental mosaicism).

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

“…Most PEComas are sporadic, and only a small subset is associated with the hereditary condition TSC. Recently, our group also identified a PTCH1 mutation in a patient with bilateral intra-abdominal PEComas suffering from Gorlin-Goltz syndrome ( 16 ). PEComas have been reported in only two Li–Fraumeni cases in the literature to date ( 14 , 15 ).…”

“…No. : 102026, Twist Bioscience, San Francisco, CA, USA) on a NovaSeq Illumina platform (Illumina, San Diego, CA, USA) with an average coverage of 100x ( 16 ). Data were analyzed by applying the Genome Analysis Toolkit (GATK) Germline short variant discovery (SNPs + Indels) algorithm.…”

“…Sanger validation and site-specific LOH analysis were performed as previously reported ( 16 ). Primers used for validation were as follows: TP53_ex04_FOR 5′-CTGGTAAGGACAAGGGTTGG-3′; TP53_ex04_REV: 5′-GCCAGGCATTGAAGTCTCAT-3′, and for LOH testing: TP53_int4ex4_F1: 5′-CTGGTAAGGACAAGGGTTGG-3′; TP53_int4ex4_F2: 5′-ACTTCCTGAAAACAACGTTCTG-3′; TP53_int4ex4_R1: 5′-TCATCTGGACCTGGGTCTTC-3′; TP53_int4ex4_R2: 5′-TCTGGACCTGGGTCTTCAGT-3′; TP53_int4ex4_R3: 5′-TCTGGGAGCTTCATCTGGAC-3′.…”

“…No. : A35805, Thermo Fisher Scientific, Waltham, MA, USA) was performed as previously described on an Ion Torrent next-generation sequencing platform (Ion GeneStudio S5 System, Thermo Fisher Scientific, Waltham, MA, USA) ( 16 ). Data were analyzed using Oncomine Knowledge Reporter Software (Cat.…”

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).…”