Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability

Cell Reports Medicine
Jason E McDermottClinical Tumor Analysis Consortium

Abstract

In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials.

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Citations

Oct 18, 2020·Nature Communications·Subash AdhikariMark S Baker
Feb 10, 2021·Journal of Proteome Research·Caleb M LindgrenSamuel H Payne
Mar 12, 2021·Journal of Proteome Research·Vincent DannaJason E McDermott
Oct 22, 2020·Cell Reports·Yingwei HuUNKNOWN Clinical Proteomic Tumor Analysis Consortium
May 6, 2021·Journal of Personalized Medicine·Wanda LattanziOrnella Parolini
Dec 7, 2021·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Carine RennerPamela K Kreeger

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Methods Mentioned

BETA
histone acetylation
RNA-seq
xenograft
acetylation
PCA
scraping
electrophoresis
Assay
genotyping
exome sequencing

Software Mentioned

limma
HTseq
GATK
fastq
GSEA
HiScan
Genomic Identification of Cancer ( GISTIC )
STAR
Pindel
VarScan2

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