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

McDermott, Jason; Arshad, Osama A.; Petyuk, Vladislav; Fu, Yi; Gritsenko, Marina; Clauss, Therese RW; Moore, Ronald J.; Schepmoes, Athena; Zhao, Rui; Monroe, Matthew E.; Schnaubelt, Michael; Tsai, Chia‐Feng; Payne, Samuel H.; Huang, Chen; Wang, Liang-Bo; Foltz, Steven M.; Wyczalkowski, Matthew A.; Wu, Yige; Song, Ehwang; Brewer, Molly; Thiagarajan, Mathangi; Kinsinger, Christopher R.; Robles, Ana I.; Boja, Emily S.; Rodriguez, Henry; Chan, Daniel W.; Zhang, Bing; Zhang, Zhen; Li, Ding; Smith, Richard; Liu, Tao; Rodland, Karin D.

doi:10.1016/j.xcrm.2020.100004

Cited by 64 publications

(83 citation statements)

References 69 publications

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“…Compared to normal fallopian tube, the likely cell-of-origin for HGSOC (39,40), HGSOC specimens do not have markedly increased ATM protein expression ( Fig. 1C) (41). However, phosphoproteomics analysis demonstrates that ATM kinase activity is significantly upregulated in HGSOC compared to normal fallopian tube, as indicated by increased S1981 autophosphorylation (Fig.…”

Section: Atm Is Wildtype and Upregulated In Hgsocmentioning

confidence: 90%

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

Chen

Buj

Dahl

et al. 2020

Preprint

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Background: Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy in the United States with high grade serous ovarian cancer (HGSOC) as the most commonly diagnosed subtype. While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for HGSOC patients, this strategy is limited to the 50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies. Methods:Data from HGSOC patients in The Cancer Genome Atlas (TCGA) were analyzed for ATM status, ATM and PPARa expression, and used to perform Gene Set Enrichment Analysis (GSEA). Screening data from the Dependency Map were analyzed to identify FDA-approved drugs that preferentially inhibit ATM-low cancer cells. In vitro studies were performed to determine whether ATM inhibitors synergize with the PPARa agonist fenofibrate in HGSOC cell lines. Results:The HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype in the majority of HGSOC patients and its kinase activity is upregulated compared to normal fallopian tube tissue. As high ATM has been associated with poor overall and progression-free survival, targeting ATM may be beneficial for a subset of HGSOC patients. Clinical trials of ATM inhibitors are commencing; however, ATM inhibitors are not effective as single agents. We aimed to explore novel therapeutic vulnerabilities of ATM deficient cells to develop a combinatorial therapy. Using data from TCGA, we found that multiple pathways related to metabolism are inversely correlated with ATM expression, suggesting that combining ATM inhibition and metabolic inhibition would be effective. Indeed, analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM low cell lines are more sensitive to fenofibrate, a PPARa agonist that has been previously shown to affect multiple cellular metabolic pathways. Consistently, PPARa signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Conclusions:Our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment for HGSOC.

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Section: Atm Is Wildtype and Upregulated In Hgsocmentioning

confidence: 90%

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

Chen

Buj

Dahl

et al. 2020

Preprint

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“…These activities empowered the recent creation of the International Proteogenome Consortium (ICPC; icpc.cancer.gov) 108 . Collectively, CPTAC and ICPC collaborators have comprehensively characterized 13 cancer types at the proteogenomics level, with all datasets publicly accessible [109][110][111][112][113][114][115][116][117] .…”

Section: Translating Proteomics To Precision Medicinementioning

confidence: 99%

A high-stringency blueprint of the human proteome

et al. 2020

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The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.

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“…We first wanted to know how these measurements relate to each other to determine the extent that one measurement can stand as a proxy for overall LINE-1 "activity." We reanalyzed data from the CPTAC project to quantify LINE-1 mRNA, ORF1p (L1RE1) and ORF1p S18, S27, S33 and T203 phosphorylation in 5 cancer types: breast (n=94; (Krug et al, 2020) ), ovarian (n=97; (McDermott et al, 2020) ), colon (n=93) (Vasaikar et al, 2019) , clear cell kidney (n=106) (Clark et al, 2019) and endometrial (n=88) (Dou et al, 2020) . We also used the Mobile Element Locator Tool (MELT) to quantify somatic LINE-1 insertions in kidney and endometrial tumors, where matched tumor and whole blood WGS was available.…”

Section: Quantifications Of Line-1 Expression Orf1p Phosphorylationmentioning

confidence: 99%

“…For colon cancer, the CNV score was recalculated according to the description provided (Vasaikar et al, 2019). For ovarian cancer, a global CNV score was calculated from gene level CNV provided by the CPTAC working group (McDermott et al, 2020). First, any gene overlapping another gene with a smaller leftmost coordinate was removed.…”

Section: Estimation Of Global Cnvmentioning

confidence: 99%

“…Transcriptomic and genomic data for CPTAC 3 (endometrial and kidney cancers) can be found in the Genomic Data Commons ( https://gdc.cancer.gov/ ). Additionally data for each cancer type can be found in the corresponding publication: colon (Vasaikar et al, 2019), breast (Krug et al, 2020), ovarian (McDermott et al, 2020), endometrial (Dou et al, 2020), and kidney (Clark et al, 2019). L1EM code can be found at https://github.com/FenyoLab/L1EM .…”

Section: Data and Code Availabilitymentioning

confidence: 99%

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LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

McKerrow

Wang

Mita

et al. 2020

Preprint

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Retrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.

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

Cited by 64 publications

References 69 publications

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

A high-stringency blueprint of the human proteome

LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

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