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


Autoři: Bhuvana A. Setty aff001;  Goodwin G. Jinesh aff003;  Michael Arnold aff004;  Fredrik Pettersson aff006;  Chia-Ho Cheng aff006;  Ling Cen aff006;  Sean J. Yoder aff007;  Jamie K. Teer aff006;  Elsa R. Flores aff008;  Damon R. Reed aff003;  Andrew S. Brohl aff003
Působiště autorů: Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, Ohio, United States of America aff001;  Department of Pediatrics, The Ohio State University Wexner Medical Center Columbus, Ohio, United States of America aff002;  Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Florida, United States of America aff003;  Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America aff004;  Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America aff005;  Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America aff006;  Molecular Genomics Core Facility, Moffitt Cancer Center, Tampa, Florida, United States of America aff007;  Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, United States of America aff008;  Adolescent and Young Adult Program, Moffitt Cancer Center, Tampa, Florida, United States of America aff009;  Sarcoma Department, Moffitt Cancer Center, Tampa, Florida, United States of America aff010
Vyšlo v časopise: The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008642
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008642

Souhrn

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 hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.

Klíčová slova:

Cell fusion – DNA transcription – Hispanic people – Chromosome structure and function – MicroRNAs – Molecular genetics – RNA sequencing – Somatic mutation


Zdroje

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