التفاصيل البيبلوغرافية
| العنوان: |
The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss. |
| المؤلفون: |
Setty, Bhuvana A., Jinesh, Goodwin G., Arnold, Michael, Pettersson, Fredrik, Cheng, Chia-Ho, Cen, Ling, Yoder, Sean J., Teer, Jamie K., Flores, Elsa R., Reed, Damon R., Brohl, Andrew S. |
| المصدر: |
PLoS Genetics; 4/20/2020, Vol. 16 Issue 4, p1-18, 18p |
| مصطلحات موضوعية: |
SARCOMA, NUCLEOTIDE sequence, LIVER, NUCLEOTIDE sequencing, ANAPLASTIC lymphoma kinase, MICRORNA, PLANT chromosomes, LIVER cells |
| مستخلص: |
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. Author summary: We perform the most comprehensive molecular analysis to date of undifferentiated embryonal sarcoma of the liver, utilizing whole exome sequencing, RNA sequencing, miRNA sequencing, and SNP arrays. We find that UESL tumors harbor aberrant transcriptional start sites within C19MC region that is driven by structural rearrangement, leading to extreme overexpression of C19MC miRNAs. We further find that C19MC miRNAs negatively correlate with TP53 and K-Ras regulatory miRNAs. UESL also harbors highly recurrent TP53 mutation or copy number loss. Therefore, we provide for the first time a genomic landscape of UESL and describe cellular consequences of the discovered foundational genomic changes. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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