Cancer-Related Ischemic Stroke Has a Distinct Blood mRNA Expression Profile

Babak B Navi, Ryna Mathias, Carla P Sherman, Julia Wolfe, Hooman Kamel, Scott T Tagawa, Ashish Saxena, Allyson J Ocean, Costantino Iadecola, Lisa M DeAngelis, Mitchell S V Elkind, Heather Hull, Glen C Jickling, Frank R Sharp, Bradley P Ander, Boryana Stamova, Babak B Navi, Ryna Mathias, Carla P Sherman, Julia Wolfe, Hooman Kamel, Scott T Tagawa, Ashish Saxena, Allyson J Ocean, Costantino Iadecola, Lisa M DeAngelis, Mitchell S V Elkind, Heather Hull, Glen C Jickling, Frank R Sharp, Bradley P Ander, Boryana Stamova

Abstract

Background and Purpose- Comorbid cancer is common in patients with acute ischemic stroke (AIS). As blood mRNA profiles can distinguish AIS mechanisms, we hypothesized that cancer-related AIS would have a distinctive gene expression profile. Methods- We evaluated 4 groups of 10 subjects prospectively enrolled at 3 centers from 2009 to 2018. This included the group of interest with active solid tumor cancer and AIS and 3 control groups with active cancer only, AIS only, or vascular risk factors only. Subjects in the AIS-only and cancer-only groups were matched to subjects in the cancer-stroke group by age, sex, and cancer type (if applicable). Subjects in the vascular risk factor group were matched to subjects in the cancer-stroke and stroke-only groups by age, sex, and vascular risk factors. Blood was drawn 72 to 120 hours after stroke. Total RNA was processed using 3' mRNA sequencing. ANOVA and Fisher least significant difference contrast methods were used to estimate differential gene expression between groups. Results- In the cancer-stroke group, 50% of strokes were cryptogenic. All groups had differentially expressed genes that could distinguish among them. Comparing the cancer-stroke group to the stroke-only group and after accounting for cancer-only genes, 438 genes were differentially expressed, including upregulation of multiple genes/pathways implicated in autophagy signaling, immunity/inflammation, and gene regulation, including IL (interleukin)-1, interferon, relaxin, mammalian target of rapamycin signaling, SQSTMI1 (sequestosome-1), and CREB1 (cAMP response element binding protein-1). Conclusions- This study provides evidence for a distinctive molecular signature in blood mRNA expression profiles of patients with cancer-related AIS. Future studies should evaluate whether blood mRNA can predict detection of occult cancer in patients with AIS. Clinical Trial Registration- URL: https://ichgcp.net/clinical-trials-registry/NCT02604667" title="See in ClinicalTrials.gov">NCT02604667.

Keywords: gene expression; humans; neoplasms; risk factors; stroke.

Figures

Figure 1
Figure 1
A-B. Principal component analysis and unsupervised hierarchical clustering of 1,797 differentially expressed genes between the cancer-stroke (CS) and vascular risk factor control (VRFC) groups. C-D. Principal component analysis and unsupervised hierarchical clustering of 1,197 differentially expressed genes between the stroke-only (SO) and VRFC groups. Orange denotes CS group, gray denotes VRFC group, and blue denotes SO group. Red represents high expressed genes; green represents low expressed genes.
Figure 1
Figure 1
A-B. Principal component analysis and unsupervised hierarchical clustering of 1,797 differentially expressed genes between the cancer-stroke (CS) and vascular risk factor control (VRFC) groups. C-D. Principal component analysis and unsupervised hierarchical clustering of 1,197 differentially expressed genes between the stroke-only (SO) and VRFC groups. Orange denotes CS group, gray denotes VRFC group, and blue denotes SO group. Red represents high expressed genes; green represents low expressed genes.
Figure 1
Figure 1
A-B. Principal component analysis and unsupervised hierarchical clustering of 1,797 differentially expressed genes between the cancer-stroke (CS) and vascular risk factor control (VRFC) groups. C-D. Principal component analysis and unsupervised hierarchical clustering of 1,197 differentially expressed genes between the stroke-only (SO) and VRFC groups. Orange denotes CS group, gray denotes VRFC group, and blue denotes SO group. Red represents high expressed genes; green represents low expressed genes.
Figure 1
Figure 1
A-B. Principal component analysis and unsupervised hierarchical clustering of 1,797 differentially expressed genes between the cancer-stroke (CS) and vascular risk factor control (VRFC) groups. C-D. Principal component analysis and unsupervised hierarchical clustering of 1,197 differentially expressed genes between the stroke-only (SO) and VRFC groups. Orange denotes CS group, gray denotes VRFC group, and blue denotes SO group. Red represents high expressed genes; green represents low expressed genes.
Figure 2
Figure 2
A-B. Principal component analysis and unsupervised hierarchical clustering of 448 differentially expressed genes between the cancer-stroke (CS) and stroke-only (SO) groups. Orange denotes CS group; blue denotes SO group. Red represents high expressed genes; green represents low expressed genes. C. Overlap between the differentially expressed genes in the CS vs. SO groups and the cancer-only (CO) vs. the vascular risk factor control (VRFC) groups. The table represents the canonical pathways that are significantly overrepresented when comparing CS subjects to SO subjects. Asterisk denotes pathways predicted to be activated in CS vs. SO.
Figure 2
Figure 2
A-B. Principal component analysis and unsupervised hierarchical clustering of 448 differentially expressed genes between the cancer-stroke (CS) and stroke-only (SO) groups. Orange denotes CS group; blue denotes SO group. Red represents high expressed genes; green represents low expressed genes. C. Overlap between the differentially expressed genes in the CS vs. SO groups and the cancer-only (CO) vs. the vascular risk factor control (VRFC) groups. The table represents the canonical pathways that are significantly overrepresented when comparing CS subjects to SO subjects. Asterisk denotes pathways predicted to be activated in CS vs. SO.
Figure 2
Figure 2
A-B. Principal component analysis and unsupervised hierarchical clustering of 448 differentially expressed genes between the cancer-stroke (CS) and stroke-only (SO) groups. Orange denotes CS group; blue denotes SO group. Red represents high expressed genes; green represents low expressed genes. C. Overlap between the differentially expressed genes in the CS vs. SO groups and the cancer-only (CO) vs. the vascular risk factor control (VRFC) groups. The table represents the canonical pathways that are significantly overrepresented when comparing CS subjects to SO subjects. Asterisk denotes pathways predicted to be activated in CS vs. SO.

Source: PubMed

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