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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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Related in: MedlinePlus

Major upstream regulators, TGFB1, MYC, and TP53 enriched by differentially expressed genes in our dataset. (a)TGFB1 upstream regulator of networks where the gene enrichment P values for differential expression was highly significant. (b)MYC primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant. (c)TP53 primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant.
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Fig2: Major upstream regulators, TGFB1, MYC, and TP53 enriched by differentially expressed genes in our dataset. (a)TGFB1 upstream regulator of networks where the gene enrichment P values for differential expression was highly significant. (b)MYC primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant. (c)TP53 primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant.

Mentions: To help interpret these results, we assessed upstream regulators using IPA. The top upstream of molecules associated with the de-regulated genes in our data were TGFB1 (P = 8.14 × 10-46), beta-estradiol (P = 1.21 × 10-41), TP53 (P = 1.90 × 10-38), CDKN1A (P = 1.41 × 10-37), and MYC (P = 4.59 × 10-36) (Table 4). It is interesting to note that TP53, which was predicted to be inhibited in our data, was actually up-regulated, although only significant in Group A and therefore not included in the analysis. This suggests that an indirect relationship with other molecules could have resulted in this shift in expected activation. The major network regulators regulated by the TGFB1, TP53, and MYC are shown in Figure 2a, b, and c, respectively. There were 20 mechanistic network regulators for TGFB1, 20 for TP53, and 22 for MYC that were significantly enriched in our data based on the number of differentially expressed genes belonging directly and indirectly to these networks (Additional file 6: Table S3 shows genes in our data that were directly or indirectly regulated by these pathways).Table 4


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

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

Major upstream regulators, TGFB1, MYC, and TP53 enriched by differentially expressed genes in our dataset. (a)TGFB1 upstream regulator of networks where the gene enrichment P values for differential expression was highly significant. (b)MYC primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant. (c)TP53 primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Major upstream regulators, TGFB1, MYC, and TP53 enriched by differentially expressed genes in our dataset. (a)TGFB1 upstream regulator of networks where the gene enrichment P values for differential expression was highly significant. (b)MYC primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant. (c)TP53 primary upstream regulator of networks where the gene enrichment P value for differential expression was highly significant.
Mentions: To help interpret these results, we assessed upstream regulators using IPA. The top upstream of molecules associated with the de-regulated genes in our data were TGFB1 (P = 8.14 × 10-46), beta-estradiol (P = 1.21 × 10-41), TP53 (P = 1.90 × 10-38), CDKN1A (P = 1.41 × 10-37), and MYC (P = 4.59 × 10-36) (Table 4). It is interesting to note that TP53, which was predicted to be inhibited in our data, was actually up-regulated, although only significant in Group A and therefore not included in the analysis. This suggests that an indirect relationship with other molecules could have resulted in this shift in expected activation. The major network regulators regulated by the TGFB1, TP53, and MYC are shown in Figure 2a, b, and c, respectively. There were 20 mechanistic network regulators for TGFB1, 20 for TP53, and 22 for MYC that were significantly enriched in our data based on the number of differentially expressed genes belonging directly and indirectly to these networks (Additional file 6: Table S3 shows genes in our data that were directly or indirectly regulated by these pathways).Table 4

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