Dataset Information

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers.

ABSTRACT:

Background

Despite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.

Methods

In a retrospective bioinformatics analysis involving patients with liver cancer (n?=?839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n?=?520), renal papillary cell (n?=?290), lung (n?=?515), pancreas (n?=?178) and endometrial (n?=?370).

Results

The 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR)?=?1.82, P?=?0.006; HR?=?1.84, P?=?0.008 and HR?=?2.67, P?=?0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR?=?2.36, P?=?0.0003; HR?=?2.43, P?=?0.0002 and HR?=?3.45, P?=?0.0007), head and neck (HR?=?1.64, P?=?0.004), renal papillary cell (HR?=?2.31, P?=?0.04), lung (HR?=?1.45, P?=?0.03), pancreas (HR?=?1.96, P?=?0.006) and endometrial (HR?=?2.33, P?=?0.003). Receiver operating characteristic analyses demonstrated both signatures superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.

Conclusions

This study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n?=?2712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.

SUBMITTER: Chang WH

PROVIDER: S-EPMC6327401 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers.

Chang Wai Hoong WH Forde Donall D Lai Alvina G AG

Journal of translational medicine 20190109 1

<h4>Background</h4>Despite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.<h4>Methods</h4>In a retrospective bioinformatics analysis involving patients with liver cancer (n = 839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we ...[more]

PMID: 30626396

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Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

Dataset Information

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers.

Background

Methods

Results

Conclusions

Publications

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers.

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