The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss

Abstract

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC

Regulation of MYO18B mRNA by a network of C19MC miRNA-520G, IFN-γ, CEBPB, p53 and bFGF in hepatocellular carcinoma

“…C19MC is a cluster of 46 miRNAs located at chr19q13.42 16 , 17 . C19MC miRNAs have been implicated in multiple cancer types such as breast cancer 17 , embryonal tumors with multilayered rosettes (ETMRs) 18 , infantile hemangioma 19 , thyroid adenomas 20 , testicular germ cell tumors 21 , parathyroid tumors 22 , undifferentiated embryonal sarcoma of the liver (UESL) 23 , including hepatocellular carcinoma 24 – 26 . However, the role of C19MC miRNAs in the context of MYO18B gene transcription is not known to date.…”

“…tumors 22 , undifferentiated embryonal sarcoma of the liver (UESL) 23 , including hepatocellular carcinoma [24][25][26] . However, the role of C19MC miRNAs in the context of MYO18B gene transcription is not known to date.…”

The Roles of Imprinted SLC22A18 and SLC22A18AS Gene Overexpression Caused by Promoter CpG Island Hypomethylation as Diagnostic and Prognostic Biomarkers for Non-Small Cell Lung Cancer Patients

“…Accordingly, a loss of genomic imprinting has been reported in a wide range of tumors, such as Wilms’ tumors, lung carcinomas, neuroblastomas, acute myeloblastic leukemias, rhabdomyosarcomas, and sporadic osteosarcomas [ 21 ]. In fact, many imprinted genes tend to be organized in large clusters (e.g., IGF2-H19, DLK1-DIO3 or C19MC), suggesting the potential involvement of higher order regulatory elements for these regions [ 14 , 22 , 23 , 24 , 25 , 26 , 27 ]. A better-characterized imprinted cluster in cancer is the chromosome 11p15.5 region.…”

Pediatric Primary Hepatic Tumors: Diagnostic Considerations

“…Case studies and series have identified mutations in the DNA-binding domain of the TP53 gene [ 161 , 172 ] as well as somatic mutations in WDR25, CMTM1, and DNHA17 [ 173 ], although these are reported in single cases and further investigation into the exact pathogenesis is required [ 30 ]. Whole exome sequencing was performed in a sample of 14 patients with UESL, which found that the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss was a highly recurrent genomic feature of UESL [ 171 ].…”