Background
Methods
Cancer cohorts
Copy number alterations analyses
Defining ClockLoss and ClockGain gene sets and calculating clock and hypoxia scores
Survival, differential expression and multidimensional scaling analyses
Pathway enrichment and transcription factor analyses
Results
Integrated genomic and transcriptomic analyses reveal conserved patterns of putative loss-and gain-of-function mutations in circadian clock genes
Tumour suppressive and oncogenic potential of the circadian clock are context dependent
Hazard ratio (95% CI) | P-value | |
---|---|---|
All gliomas (ClockLost) | Univariate | |
Q2 vs. Q1 | 0.393 (0.285–0.543) | < 0.0001 |
Q3 vs. Q1 | 0.274 (0.193–0.387) | < 0.0001 |
Q4 vs. Q1 | 0.188 (0.127–0.278) | < 0.0001 |
All gliomas (ClockGain) | Univariate | |
Q2 vs. Q1 | 1.272 (0.813–1.991) | 0.29 |
Q3 vs. Q1 | 2.931 (1.951–4.402) | < 0.0001 |
Q4 vs. Q1 | 3.961 (2.668–5.882) | < 0.0001 |
Astrocytoma (ClockGain) | Univariate | |
Q2 vs. Q1 | 0.59 (0.242–1.468) | 0.26 |
Q3 vs. Q1 | 1.423 (0.65–3.109) | 0.38 |
Q4 vs. Q1 | 3.048 (1.514–6.137) |
0.0018
|
Oligodendroglioma (ClockGain) | Univariate | |
Q2 vs. Q1 | 0.947 (0.362–2.474) | 0.91 |
Q3 vs. Q1 | 1.184 (0.475–2.951) | 0.72 |
Q4 vs. Q1 | 2.764 (1.194–6.400) |
0.018
|
Pan-kidney (ClockLost) | Univariate | |
Q2 vs. Q1 | 0.783 (0.547–1.121) | 0.18 |
Q3 vs. Q1 | 0.801 (0.568–1.131) | 0.21 |
Q4 vs. Q1 | 0.520 (0.352–0.768) |
0.001
|
TNM staging | 2.095 (1.858–2.361) | < 0.0001 |
Multivariate | ||
Q2 vs. Q1 | 0.783 (0.543–1.129) | 0.18 |
Q3 vs. Q1 | 0.764 (0.537–1.089) | 0.14 |
Q4 vs. Q1 | 0.569 (0.383–0.847) |
0.0055
|
TNM staging | 2.085 (1.848–2.354) | < 0.0001 |
Pan-kidney (ClockGain) | Univariate | |
Q2 vs. Q1 | 1.237 (0.838–1.825) | 0.28 |
Q3 vs. Q1 | 1.222 (0.828–1.803) | 0.31 |
Q4 vs. Q1 | 1.890 (1.311–2.725) |
0.00066
|
Multivariate | ||
Q2 vs. Q1 | 1.177 (0.790–1.752) | 0.42 |
Q3 vs. Q1 | 1.429 (0.961–2.124) | 0.078 |
Q4 vs. Q1 | 1.941 (1.333–2.826) |
0.00054
|
TNM staging | 2.092 (1.857–2.357) | < 0.0001 |
Clear cell renal cell (ClockLost) | Univariate | |
Q2 vs. Q1 | 0.608 (0.416–0.888) |
0.01
|
Q3 vs. Q1 | 0.546 (0.361–0.795) |
0.0019
|
Q4 vs. Q1 | 0.292 (0.179–0.474) | < 0.0001 |
TNM staging | 1.87 (1.641–2.132) | < 0.0001 |
Multivariate | ||
Q2 vs. Q1 | 0.653 (0.447–0.955) |
0.027
|
Q3 vs. Q1 | 0.667 (0.448–0.993) |
0.046
|
Q4 vs. Q1 | 0.433 (0.265–0.708) |
0.00085
|
TNM staging | 1.798 (1.572–2.058) | < 0.0001 |
Clear cell renal cell (ClockGain) | Univariate | |
Q2 vs. Q1 | 1.243 (0.799–1.933) | 0.33 |
Q3 vs. Q1 | 1.001 (0.640–1.564) | 0.99 |
Q4 vs. Q1 | 1.775 (1.177–2.678) |
0.0062
|
Multivariate | ||
Q2 vs. Q1 | 1.222 (0.786–1.901) | 0.37 |
Q3 vs. Q1 | 1.284 (0.818–2.017) | 0.28 |
Q4 vs. Q1 | 1.856 (1.230–2.802) |
0.0032
|
TNM staging | 1.874 (1.642–2.138) | < 0.0001 |
Bladder (ClockLost) | Univariate | |
Q2 vs. Q1 | 1.088 (0.593–1.999) | 0.78 |
Q3 vs. Q1 | 1.478 (0.828–2.640) | 0.19 |
Q4 vs. Q1 | 2.081 (1.198–3.614) |
0.0093
|
TNM staging | 1.679 (1.323–2.131) | < 0.0001 |
Multivariate | ||
Q2 vs. Q1 | 1.059 (0.577–1.946) | 0.85 |
Q3 vs. Q1 | 1.357 (0.759–2.426) | 0.31 |
Q4 vs. Q1 | 1.776 (1.018–3.099) |
0.043
|
TNM staging | 1.609 (1.263–2.050) |
1.20E−04
|
Stomach (ClockLost) | Univariate | |
Q2 vs. Q1 | 0.761 (0.389–1.485) | 0.43 |
Q3 vs. Q1 | 1.143 (0.615–2.127) | 0.67 |
Q4 vs. Q1 | 2.155 (1.255–3.702) |
0.0054
|
TNM staging | 1.372 (1.067–1.765) |
0.038
|
Multivariate | ||
Q2 vs. Q1 | 0.731 (0.374–1.428) | 0.36 |
Q3 vs. Q1 | 1.133 (0.609–2.107) | 0.69 |
Q4 vs. Q1 | 2.070 (1.205–3.557) |
0.0084
|
TNM staging | 1.354 (1.054–1.739) |
0.018
|
Lung (ClockGain) | Univariate | |
Q2 vs. Q1 | 1.633 (0.987–2.699) | 0.056 |
Q3 vs. Q1 | 1.604 (0.973–2.644) | 0.064 |
Q4 vs. Q1 | 2.023 (1.224–3.343) |
0.006
|
TNM staging | 1.597 (1.364–1.870) | < 0.0001 |
Multivariate | ||
Q2 vs. Q1 | 1.604 (0.971–2.652) | 0.065 |
Q3 vs. Q1 | 1.434 (0.868–2.370) | 0.16 |
Q4 vs. Q1 | 1.832 (1.108–3.029) |
0.018
|
TNM staging | 1.584 (1.348–1.861) | < 0.0001 |
Pancreas (ClockGain) | Univariate | |
Q2 vs. Q1 | 1.791 (0.849–3.779) | 0.13 |
Q3 vs. Q1 | 1.602 (0.740–3.470) | 0.23 |
Q4 vs. Q1 | 3.034 (1.492–6.168) |
0.0022
|
TNM staging | 1.339 (0.897–1.998) | 0.153 |
Multivariate | ||
Q2 vs. Q1 | 1.712 (0.803–3.652) | 0.16 |
Q3 vs. Q1 | 1.584 (0.731–3.430) | 0.24 |
Q4 vs. Q1 | 2.890 (1.399–5.970) |
0.0042
|
TNM staging | 1.143 (0.756–1.728) | 0.52 |
ClockLoss and ClockGain are independent prognostic factors
Dysregulated circadian timekeeping is associated with malignant progression
Disease phenotypes of tumours with deranged circadian homeostasis are aggravated by hypoxia
Hazard ratio (95% CI) | P-value | |
---|---|---|
Glioma (ClockLoss) | ||
Low ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 7.218 (4.234–12.304) | < 0.0001 |
High ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 3.138 (1.733–5.683) |
0.00016
|
High ClockLoss and low hypoxia score vs. low ClockLoss and low hypoxia score | 1.114 (0.617–2.014) | 0.72 |
Pan-kidney (ClockLoss) | ||
Low ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 2.512 (1.732–3.643) | < 0.0001 |
High ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 1.580 (1.094–2.282) |
0.0148
|
High ClockLoss and low hypoxia score vs. low ClockLoss and low hypoxia score | 0.695 (0.423–1.122) | 0.14 |
Clear cell renal cell (ClockLoss) | ||
Low ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 1.893 (1.207–2.969) |
0.0054
|
High ClockLoss and high hypoxia score vs. low ClockLoss and low hypoxia score | 1.285 (0.761–2.170) | 0.35 |
High ClockLoss and low hypoxia score vs. low ClockLoss and low hypoxia score | 0.796 (0.479–1.324) | 0.38 |
Glioma (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 9.210 (6.182–13.721) | < 0.0001 |
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.550 (0.917–2.622) | 0.11 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 3.317 (2.105–5.228) | < 0.0001 |
Astrocytoma (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 5.684 (2.770–11.662) | < 0.0001 |
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.451 (0.527–3.998) | 0.47 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 2.378 (0.985–5.736) | 0.054 |
Oligodendroglioma (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 4.085 (1.656–10.068) |
0.0022
|
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.218 (0.439–3.374) | 0.71 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 1.541 (0.581–4.091) | 0.38 |
Pan-kidney (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 3.079 (2.040–4.646) | < 0.0001 |
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.742 (1.089–2.785) |
0.021
|
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 2.823 (1.850–4.307) | < 0.0001 |
Clear cell renal cell (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 1.877 (1.222–2.884) |
0.0041
|
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.189 (0.742–1.908) | 0.47 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 1.630 (1.043–2.546) |
0.032
|
Lung (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 2.037 (1.327–3.129) |
0.0012
|
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 1.332 (0.755–2.351) | 0.33 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 1.995 (1.221–3.258) |
0.0058
|
Pancreas (ClockGain) | ||
High ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 1.976 (1.163–3.357) |
0.012
|
High ClockGain and low hypoxia score vs. low ClockGain and low hypoxia score | 0.852 (0.344–2.110) | 0.73 |
Low ClockGain and high hypoxia score vs. low ClockGain and low hypoxia score | 0.893 (0.397–2.009) | 0.79 |