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

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.

SUBMITTER: McDermott JE

PROVIDER: S-EPMC7289043 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

McDermott Jason E JE Arshad Osama A OA Petyuk Vladislav A VA Fu Yi Y Gritsenko Marina A MA Clauss Therese R TR Moore Ronald J RJ Schepmoes Athena A AA Zhao Rui R Monroe Matthew E ME Schnaubelt Michael M Tsai Chia-Feng CF Payne Samuel H SH Huang Chen C Wang Liang-Bo LB Foltz Steven S Wyczalkowski Matthew M Wu Yige Y Song Ehwang E Brewer Molly A MA Thiagarajan Mathangi M Kinsinger Christopher R CR Robles Ana I AI Boja Emily S ES Rodriguez Henry H Chan Daniel W DW Zhang Bing B Zhang Zhen Z Ding Li L Smith Richard D RD Liu Tao T Rodland Karin D KD

Cell reports. Medicine 20200410 1

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 signif ...[more]

PMID: 32529193

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Project description:Study questionWhat is the prevalence of somatic chromosomal instability among women with idiopathic primary ovarian insufficiency (POI)?Summary answerA subset of women with idiopathic POI may have functional impairment in DNA repair leading to chromosomal instability in their soma.What is known alreadyThe formation and repair of DNA double-strand breaks during meiotic recombination are fundamental processes of gametogenesis. Oocytes with compromised DNA integrity are susceptible to apoptosis which could trigger premature ovarian aging and accelerated wastage of the human follicle reserve. Genomewide association studies, as well as whole exome sequencing, have implicated multiple genes involved in DNA damage repair. However, the prevalence of defective DNA damage repair in the soma of women with POI is unknown.Study design, size, durationIn total, 46 women with POI and 15 family members were evaluated for excessive mitomycin-C (MMC)-induced chromosome breakage. Healthy fertile females (n = 20) and two lymphoblastoid cell lines served as negative and as positive controls, respectively.Participants/materials, setting, methodsWe performed a pilot functional study utilizing MMC to assess chromosomal instability in the peripheral blood of participants. A high-resolution array comparative genomic hybridization (aCGH) was performed on 16 POI patients to identify copy number variations (CNVs) for a set of 341 targeted genes implicated in DNA repair.Main results and the role of chanceArray CGH revealed three POI patients (3/16, 18.8%) with pathogenic CNVs. Excessive chromosomal breakage suggestive of a constitutional deficiency in DNA repair was detected in one POI patient with the 16p12.3 duplication. In two patients with negative chromosome breakage analysis, aCGH detected a Xq28 deletion comprising the Centrin EF-hand Protein 2 (CETN2) and HAUS Augmin Like Complex Subunit 7 (HAUS7) genes essential for meiotic DNA repair, and a duplication in the 3p22.2 region comprising a part of the ATPase domain of the MutL Homolog 1 (MLH1) gene.Limitations reasons for cautionPeripheral lymphocytes, used as a surrogate tissue to quantify induced chromosome damage, may not be representative of all the affected tissues. Another limitation pertains to the MMC assay which detects homologous repair pathway defects and does not test deficiencies in other DNA repair pathways.Wider implications of the findingsOur results provide evidence for functional impairment of DNA repair in idiopathic POI, which may predispose the patients to other DNA repair-related conditions such as accelerated aging and/or cancer susceptibility.Study funding/competing interest(s)Funding was provided by the National Institute of Child Health and Human Development. There were no competing interests to declare.

Dataset Information

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

Publications

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

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