Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Yang, Lingjian; Roberts, D. F.; Takhar, Mandeep; Erho, Nicholas; Bibby, Becky A.S.; Thiruthaneeswaran, Niluja; Bhandari, Vinayak; Cheng, Wei Chen; Haider, Syed; McCorry, Amy M B; McArt, Darragh G.; Jain, Suneil; Alshalalfa, Mohammed; Ross, Ashley E.; Schaffer, Edward; Den, Robert B.; Karnes, R. Jeffrey; Klein, Eric A.; Hoskin, Peter; Freedland, Stephen J.; Lamb, Alastair; Neal, David E.; Buffa, Francesca M.; Bristow, Robert G.; Boutros, Paul C.; Davicioni, Elai; Choudhury, Ananya; West, Catharine M L

doi:10.1016/j.ebiom.2018.04.019

Cited by 130 publications

(139 citation statements)

References 54 publications

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“…across cancers using the lme4 package (v1. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For each feature of interest we compared a full model (i.e., a model with the feature of interest) to a null model (i.e.…”

Section: Linear Mixed-effect Modelsmentioning

confidence: 99%

“…Hypoxia can also be caused by changes in oxygen demand: altered tumour metabolism 6,7 can increase intra-cellular demand for oxygen, potentially extending hypoxia signalling to liquid tumours. The adaptation of tumour cells to this imbalance in oxygen supply and demand is associated with poor clinical prognosis in several cancer types, attributed at least in part to hypoxia-associated genomic instability and clonal selection [8][9][10][11][12][13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

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Divergent mutational processes distinguish hypoxic and normoxic tumours

Bhandari

Bristow

et al. 2019

Preprint

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Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the evolutionary trajectory of tumours. Overall, this work demonstrates that hypoxia plays a critical role in shaping the genomic landscape of cancer.

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Section: Linear Mixed-effect Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Divergent mutational processes distinguish hypoxic and normoxic tumours

Bhandari

Bristow

et al. 2019

Preprint

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“…Hypoxia has been well recognised as mediating resistance to radiotherapy 36,50,77 and is arguably the most established target not yet translated into the clinic 7 . Although studies in some cancer types showed hypoxia was an adverse prognostic feature following surgery 11,58,78,79 , we showed here its widespread importance for surgery-treated patients across tumour types. Importantly, the effect of hypoxia on surgical outcomes was comparable with other omics marker.…”

Section: Discussionmentioning

confidence: 53%

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

Yang

Forker

Fjeldbo

et al. 2018

Preprint

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Hypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, ≥70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.

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“…Five of the genes were prognostic in a single cohort and SPRED1 had no prognostic significance (Table III). We further compared TWIST1 to a recently published hypoxia-gene associated prognostic signature for prostate cancer [22]. The 28-gene prognostic signature was derived from the TCGA cohort, and had a significant proportion of genes absent in Sboner et al cohort.…”

Section: Resultsmentioning

confidence: 99%

Independence of HIF1a and androgen signaling pathways in prostate cancer

Tran

Bibby

Yang

et al. 2019

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Androgen signaling drives prostate cancer progression and is a therapeutic target.Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

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Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Cited by 130 publications

References 54 publications

Divergent mutational processes distinguish hypoxic and normoxic tumours

Divergent mutational processes distinguish hypoxic and normoxic tumours

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

Independence of HIF1a and androgen signaling pathways in prostate cancer

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