Dual prognostic role for 2-oxoglutarate oxygenases in ten diverse cancer types: Implications for cell cycle regulation and cell adhesion maintenance

2019

Preprint

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The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (Clock Loss ) and gainof-function (Clock Gain ) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. Clock Loss and Clock Gain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of Clock Loss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic Clock Gain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive Clock Loss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. Clock Loss and Clock Gain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with firstline treatments. circadian clock | hypoxia | oncogene | tumour suppressor | gain-of-function | loss-of-function | pan-cancer | glioma | renal cancer Correspondence: alvina.lai@ndm.ox.ac.uk

Section: Dysregulated Circadian Timekeeping Is Associated With Malignsupporting

confidence: 89%

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

2019

Preprint

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“…TNM: tumor, node, metastasis. AUCs for TNM staging were in accordance with previous publications employing TCGA datasets 19,20 .…”

Section: Resultssupporting

confidence: 89%

Transcriptional landscape of DNA repair genes underpins a pan-cancer prognostic signature associated with cell cycle dysregulation and tumor hypoxia

2019

Preprint

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Overactive DNA repair contributes to therapeutic resistance in cancer. However, pan-cancer comparative studies investigating the contribution of all DNA repair genes in cancer progression employing an integrated approach have remained limited. We performed a multicohort retrospective analysis to determine the prognostic significance of 138 DNA repair genes in 16 cancer types (n=16,225). Cox proportional hazards analyses revealed a significant variation in the number of prognostic genes between cancers; 81 genes were prognostic in clear cell renal cell carcinoma while only two genes were prognostic in glioblastoma. We reasoned that genes that were commonly prognostic in highly correlated cancers revealed by Spearman’s correlation analysis could be harnessed as a molecular signature for risk assessment. A 10-gene signature, uniting prognostic genes that were common in highly correlated cancers, was significantly associated with overall survival in patients with clear cell renal cell (P<0.0001), papillary renal cell (P=0.0007), liver (P=0.002), lung (P=0.028), pancreas (P=0.00013) or endometrial (P=0.00063) cancers. Receiver operating characteristic analyses revealed that a combined model of the 10-gene signature and tumor staging outperformed either classifiers when considered alone. Multivariate Cox regression models incorporating additional clinicopathological features revealed that the signature was an independent predictor of overall survival. Tumor hypoxia is associated with adverse outcomes. Consistent across all six cancers, patients with high 10-gene and high hypoxia scores had significantly higher mortality rates compared to those with low 10-gene and low hypoxia scores. Functional enrichment analyses revealed that high mortality rates in patients with high 10-gene scores were attributable to an overproliferation phenotype. Death risk in these patients was further exacerbated by concurrent mutations of a cell cycle checkpoint protein, TP53. The 10-gene signature identified tumors with heightened DNA repair ability. This information has the potential to radically change prognosis through the use of adjuvant DNA repair inhibitors with chemotherapeutic drugs.

“…Hypoxia is a universal feature in almost all solid malignancies due to the formation of aberrant tumor microvasculature . As an adaptation strategy to hypoxic environments, tumor cells need to reprogram their metabolic requirements to survive .…”

Section: Resultsmentioning

confidence: 99%

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Annals of the New York Academy of Sciences

2019

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Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases, including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet little is known about the interactions between genetic and transcriptional events of pathway genes in a pan‐cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 genes demonstrating mutually exclusive patterns of loss‐ and gain‐of‐function phenotypes. These genes successfully predicted patient survival rates in bladder, renal, glioma, liver, and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically relevant relationships between PPARs and hypoxia were observed, where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity, and hypoxia.