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Improved survival among colon cancer patients with increased differentially expressed pathways.

Slattery ML, Herrick JS, Mullany LE, Gertz J, Wolff RK - BMC Med (2015)

Bottom Line: Of the enriched pathways, 16 were significantly associated with CRC-specific mortality, including 1 metabolic pathway and 15 signaling pathways.In all instances, having a higher DPES (i.e., more de-regulated genes) was associated with better survival.Our data suggest that having more de-regulated pathways is associated with a good prognosis and may be a reaction to key events that are disabling to tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Utah School of Medicine, 383 Colorow, Salt Lake City, 84018, USA. marty.slattery@hsc.utah.edu.

ABSTRACT

Background: Studies of colorectal cancer (CRC) have shown that hundreds to thousands of genes are differentially expressed in tumors when compared to normal tissue samples. In this study, we evaluate how genes that are differentially expressed in colon versus normal tissue influence survival.

Methods: We performed RNA-seq on tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy to determine genes that were significantly differentially expressed between tumor and normal samples. Differentially expressed genes were evaluated with Ingenuity Pathway Analysis to identify key pathways that were de-regulated. A summary differential pathway expression score (DPES) was developed to summarize hazard of dying while adjusting for age, American Joint Committee on Cancer (AJCC) stage, sex, and tumor molecular phenotype, i.e., MSI, TP53, KRAS, and CIMP.

Results: A total of 1,138 genes were up-regulated and 695 were down-regulated. These de-regulated genes were enriched for 19 Ingenuity Canonical Pathways, with the most significant pathways involving cell signaling and growth. Of the enriched pathways, 16 were significantly associated with CRC-specific mortality, including 1 metabolic pathway and 15 signaling pathways. In all instances, having a higher DPES (i.e., more de-regulated genes) was associated with better survival. Further assessment showed that individuals diagnosed at AJCC Stage 1 had more de-regulated genes than individuals diagnosed at AJCC Stage 4.

Conclusions: Our data suggest that having more de-regulated pathways is associated with a good prognosis and may be a reaction to key events that are disabling to tumor progression. Please see related article: http://dx.doi.org/10.1186/s12916-015-0307-6 .

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Significant canonical pathways identified from IPA. The pathways were statistically significant at the 0.05 level after adjustment for multiple comparisons. (a) Metabolic pathway. (b) Signaling pathway.
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Fig1: Significant canonical pathways identified from IPA. The pathways were statistically significant at the 0.05 level after adjustment for multiple comparisons. (a) Metabolic pathway. (b) Signaling pathway.

Mentions: We also linked these genes to major canonical pathways in IPA, summarized in FigureĀ 1; green refers to down-regulated genes and red to up-regulated genes within the pathway. Our significant differentially expressed genes were significantly enriched in 30 pathways (Additional file 2 shows genes in our data that were associated with these pathways). For the most part, the pathways with the majority of genes being significantly down-regulated were in metabolic pathways (Thyroid Hormone Metabolism, Malatonin Degredation I, Seratonin Degradation, Superpathway of Melatonin Degradiation, and Nicotine Degradation III and II). The other two metabolic pathways, Superpathway of Serine and Glycine Biosynthesis and Purine Nucleotides De Novo Biosynthesis, were only up-regulated. The other 22 pathways that were differentially expressed were signaling pathways, where the majority of genes were up-regulated. Exceptions to this were Complement System and Eicosanoid Signaling where the majority of de-regulated genes were down-regulated.Figure 1


Improved survival among colon cancer patients with increased differentially expressed pathways.

Slattery ML, Herrick JS, Mullany LE, Gertz J, Wolff RK - BMC Med (2015)

Significant canonical pathways identified from IPA. The pathways were statistically significant at the 0.05 level after adjustment for multiple comparisons. (a) Metabolic pathway. (b) Signaling pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4389992&req=5

Fig1: Significant canonical pathways identified from IPA. The pathways were statistically significant at the 0.05 level after adjustment for multiple comparisons. (a) Metabolic pathway. (b) Signaling pathway.
Mentions: We also linked these genes to major canonical pathways in IPA, summarized in FigureĀ 1; green refers to down-regulated genes and red to up-regulated genes within the pathway. Our significant differentially expressed genes were significantly enriched in 30 pathways (Additional file 2 shows genes in our data that were associated with these pathways). For the most part, the pathways with the majority of genes being significantly down-regulated were in metabolic pathways (Thyroid Hormone Metabolism, Malatonin Degredation I, Seratonin Degradation, Superpathway of Melatonin Degradiation, and Nicotine Degradation III and II). The other two metabolic pathways, Superpathway of Serine and Glycine Biosynthesis and Purine Nucleotides De Novo Biosynthesis, were only up-regulated. The other 22 pathways that were differentially expressed were signaling pathways, where the majority of genes were up-regulated. Exceptions to this were Complement System and Eicosanoid Signaling where the majority of de-regulated genes were down-regulated.Figure 1

Bottom Line: Of the enriched pathways, 16 were significantly associated with CRC-specific mortality, including 1 metabolic pathway and 15 signaling pathways.In all instances, having a higher DPES (i.e., more de-regulated genes) was associated with better survival.Our data suggest that having more de-regulated pathways is associated with a good prognosis and may be a reaction to key events that are disabling to tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Utah School of Medicine, 383 Colorow, Salt Lake City, 84018, USA. marty.slattery@hsc.utah.edu.

ABSTRACT

Background: Studies of colorectal cancer (CRC) have shown that hundreds to thousands of genes are differentially expressed in tumors when compared to normal tissue samples. In this study, we evaluate how genes that are differentially expressed in colon versus normal tissue influence survival.

Methods: We performed RNA-seq on tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy to determine genes that were significantly differentially expressed between tumor and normal samples. Differentially expressed genes were evaluated with Ingenuity Pathway Analysis to identify key pathways that were de-regulated. A summary differential pathway expression score (DPES) was developed to summarize hazard of dying while adjusting for age, American Joint Committee on Cancer (AJCC) stage, sex, and tumor molecular phenotype, i.e., MSI, TP53, KRAS, and CIMP.

Results: A total of 1,138 genes were up-regulated and 695 were down-regulated. These de-regulated genes were enriched for 19 Ingenuity Canonical Pathways, with the most significant pathways involving cell signaling and growth. Of the enriched pathways, 16 were significantly associated with CRC-specific mortality, including 1 metabolic pathway and 15 signaling pathways. In all instances, having a higher DPES (i.e., more de-regulated genes) was associated with better survival. Further assessment showed that individuals diagnosed at AJCC Stage 1 had more de-regulated genes than individuals diagnosed at AJCC Stage 4.

Conclusions: Our data suggest that having more de-regulated pathways is associated with a good prognosis and may be a reaction to key events that are disabling to tumor progression. Please see related article: http://dx.doi.org/10.1186/s12916-015-0307-6 .

Show MeSH
Related in: MedlinePlus