MDM2andCDK4amplifications are rare events in salivary duct carcinomas

Abstract

Salivary duct carcinoma (SDC) is an aggressive adenocarcinoma of the salivary glands associated with poor clinical outcome. SDCs are known to carry TP53 mutations in about 50%, however, only little is known about alternative pathogenic mechanisms within the p53 regulatory network. Particularly, data on alterations of the oncogenes MDM2 and CDK4 located in the chromosomal region 12q13-15 are limited in SDC, while genomic rearrangements of the adjacent HMGA2 gene locus are well documented in subsets of SDCs. We here analyzed the mutational status of the TP53 gene, genomic amplification of MDM2, CDK4 and HMGA2 rearrangement/amplification as well as protein expression of TP53 (p53), MDM2 and CDK4 in 51 de novo and ex pleomorphic adenoma SDCs.25 of 51 cases were found to carry TP53 mutations, associated with extreme positive immunohistochemical p53 staining levels in 13 cases. Three out of 51 tumors had an MDM2 amplification, one of them coinciding with a CDK4 amplification and two with a HMGA2 rearrangement/amplification. Two of the MDM2 amplifications occurred in the setting of a TP53 mutation. Two out of 51 cases showed a CDK4 amplification, one synchronously being MDM2 amplified and the other one displaying concurrent low copy number increases of both, MDM2 and HMGA2.In summary, we here show that subgroups of SDCs display genomic amplifications of MDM2 and/or CDK4, partly in association with TP53 mutations and rearrangement/amplification of HMGA2. Further research is necessary to clarify the role of chromosomal region 12q13-15 alterations in SDC tumorigenesis and their potential prognostic and therapeutic relevance.

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

“…that are commonly mutated in cancer. As described before [32][33][34] , Target enrichment was conducted by means of the GeneRead DNAseq Panel PCR V2 Kit (Qiagen). Purification and size selection steps were processed utilizing Agencourt AMPure XP magnetic beads (Beckman Coulter).…”

“…In silico tools to predict the potential deleterious impact of detected variants. The potential impact of NGS-detected variants in the coding regions was predicted using following in silico tools as reported [32][33][34] : PolyPhen-2 (v2.2.2r398) 35 , Protein Variation Effect Analyzer (PROVEAN; v1.1.3) 36 , Sorting Intolerant From Tolerant (SIFT; Ensembl 66) 37,38 , Mutation Assessor (release 3) 39 and Combined Annotation Dependent Depletion (CADD; v.1.3) 40 . The PolyPhen-2 method utilizes physical and evolutionary comparative considerations to predict amino acid changes on protein structure and function.…”

FUS–DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma

“…Next-generation sequencing (NGS) was performed applying 12.5 pmol/L library pools (2% PhiX V3 control) and the MiSeq Reagent v2 chemistry (Illumina, Inc.). NGS data analysis was performed by means of the CLC Biomedical Genomics Workbench software (CLC bio, Qiagen) as described before (39). Validation by Sanger sequencing was conducted according to standard procedures using the BigDye Terminator v3.1 Cycle Sequencing Kit (Life Technologies).…”

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…Combinations of alterations in more than one of these pathways is also relatively common in SDC [50, 57, 61]. Other less common gene expression patterns and genomic alterations have been found in small numbers of studies including few tumors, and their significance is unclear [3, 27, 31, 50, 61, 63–67]. …”

“…Percentages for each alteration were obtained by totaling the number of positive cases (by IHC or sequencing for ErbB2, EGFR, AR) divided by total cases found in the literature [3, 4, 6, 7, 15, 18, 22, 28, 33, 39, 40, 44, 49–53, 55, 57–64, 67, 86–91]. Percentages representing expression are best estimates, as positivity was defined heterogeneously among studies.…”