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Oncogenic pathway combinations predict clinical prognosis in gastric cancer.

Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim D, Chan WH, Wong WK, Bowtell D, Yeoh KG, Grabsch H, Boussioutas A, Tan P - PLoS Genet. (2009)

Bottom Line: We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers.Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior.Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups.

View Article: PubMed Central - PubMed

Affiliation: Duke-NUS Graduate Medical School, Singapore.

ABSTRACT
Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.

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Pathway interactions influence patient survival in gastric cancer.Kaplan-Meier survival analysis of Australia and Singapore cohorts (Heatmaps A and B in Figure 2) between patient groups stratified by predicted pathway activation status. Cohort 3 was not included in the survival analysis as it is much smaller than Cohorts 1 and 2 (31 tumors compared to 70 and 200), making it unreliable for statistical analysis. (A–C) Effects of individual pathways. Patients were stratified by (A) proliferation/stem cell signatures alone, (B) NF-κB signatures alone, and (C) Wnt/β-catenin signatures alone. (D) and (E) Effects of pathway interactions. Patients were stratified by (D) NF-κB and proliferation/stem cell signatures, and (E) Wnt/β-catenin and proliferation/stem cell signatures. For both the NF-κB and Wnt/β-catenin signatures, the significance of the survival difference or death hazard was markedly enhanced by the addition of pathway prediction information from the proliferation/stem cell signatures. The outcome metric was duration of overall survival. H: death hazard indicating the ratio of the mortality rate of patients showing high activation level of single pathway (or both of two pathways) to the mortality rate of patients showing low activation level of single pathway (or both of two pathways). All death hazard ratios are significant at p<0.01. CI0.95: 95% confidence intervals for death hazard ratio.
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pgen-1000676-g005: Pathway interactions influence patient survival in gastric cancer.Kaplan-Meier survival analysis of Australia and Singapore cohorts (Heatmaps A and B in Figure 2) between patient groups stratified by predicted pathway activation status. Cohort 3 was not included in the survival analysis as it is much smaller than Cohorts 1 and 2 (31 tumors compared to 70 and 200), making it unreliable for statistical analysis. (A–C) Effects of individual pathways. Patients were stratified by (A) proliferation/stem cell signatures alone, (B) NF-κB signatures alone, and (C) Wnt/β-catenin signatures alone. (D) and (E) Effects of pathway interactions. Patients were stratified by (D) NF-κB and proliferation/stem cell signatures, and (E) Wnt/β-catenin and proliferation/stem cell signatures. For both the NF-κB and Wnt/β-catenin signatures, the significance of the survival difference or death hazard was markedly enhanced by the addition of pathway prediction information from the proliferation/stem cell signatures. The outcome metric was duration of overall survival. H: death hazard indicating the ratio of the mortality rate of patients showing high activation level of single pathway (or both of two pathways) to the mortality rate of patients showing low activation level of single pathway (or both of two pathways). All death hazard ratios are significant at p<0.01. CI0.95: 95% confidence intervals for death hazard ratio.

Mentions: To assess the clinical relevance of the identified pathway subgroups, we investigated if patterns of pathway co-activation as illustrated in the heatmaps of the different cohorts might be related to patient survival. We used overall survival data from Cohort 1 and Cohort 2 and stratified patients by their predicted patterns of pathway activation. A primary GC profile was defined as showing high activation level of a pathway when the activation score was above zero – i.e. being positively associated with the pathway signature. Patient groups stratified by either the proliferation/stem cell pathway activation score alone or the NF-κB pathway activation score alone did not differ significantly regarding their overall survival (p>0.05 for proliferation/stem cell and NF-κB in both cohorts, Figure 5A and 5B). However, when the pathway activation scores were combined, patients with high activation levels of both NF-κB and proliferation/stem cell pathways had significantly shorter survival compared to patients with low activation levels of both NF-κB and proliferation/stem cell pathways (p = 0.0399 and p = 0.0109 for Cohorts 1 and 2 respectively, Figure 5D).


Oncogenic pathway combinations predict clinical prognosis in gastric cancer.

Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim D, Chan WH, Wong WK, Bowtell D, Yeoh KG, Grabsch H, Boussioutas A, Tan P - PLoS Genet. (2009)

Pathway interactions influence patient survival in gastric cancer.Kaplan-Meier survival analysis of Australia and Singapore cohorts (Heatmaps A and B in Figure 2) between patient groups stratified by predicted pathway activation status. Cohort 3 was not included in the survival analysis as it is much smaller than Cohorts 1 and 2 (31 tumors compared to 70 and 200), making it unreliable for statistical analysis. (A–C) Effects of individual pathways. Patients were stratified by (A) proliferation/stem cell signatures alone, (B) NF-κB signatures alone, and (C) Wnt/β-catenin signatures alone. (D) and (E) Effects of pathway interactions. Patients were stratified by (D) NF-κB and proliferation/stem cell signatures, and (E) Wnt/β-catenin and proliferation/stem cell signatures. For both the NF-κB and Wnt/β-catenin signatures, the significance of the survival difference or death hazard was markedly enhanced by the addition of pathway prediction information from the proliferation/stem cell signatures. The outcome metric was duration of overall survival. H: death hazard indicating the ratio of the mortality rate of patients showing high activation level of single pathway (or both of two pathways) to the mortality rate of patients showing low activation level of single pathway (or both of two pathways). All death hazard ratios are significant at p<0.01. CI0.95: 95% confidence intervals for death hazard ratio.
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pgen-1000676-g005: Pathway interactions influence patient survival in gastric cancer.Kaplan-Meier survival analysis of Australia and Singapore cohorts (Heatmaps A and B in Figure 2) between patient groups stratified by predicted pathway activation status. Cohort 3 was not included in the survival analysis as it is much smaller than Cohorts 1 and 2 (31 tumors compared to 70 and 200), making it unreliable for statistical analysis. (A–C) Effects of individual pathways. Patients were stratified by (A) proliferation/stem cell signatures alone, (B) NF-κB signatures alone, and (C) Wnt/β-catenin signatures alone. (D) and (E) Effects of pathway interactions. Patients were stratified by (D) NF-κB and proliferation/stem cell signatures, and (E) Wnt/β-catenin and proliferation/stem cell signatures. For both the NF-κB and Wnt/β-catenin signatures, the significance of the survival difference or death hazard was markedly enhanced by the addition of pathway prediction information from the proliferation/stem cell signatures. The outcome metric was duration of overall survival. H: death hazard indicating the ratio of the mortality rate of patients showing high activation level of single pathway (or both of two pathways) to the mortality rate of patients showing low activation level of single pathway (or both of two pathways). All death hazard ratios are significant at p<0.01. CI0.95: 95% confidence intervals for death hazard ratio.
Mentions: To assess the clinical relevance of the identified pathway subgroups, we investigated if patterns of pathway co-activation as illustrated in the heatmaps of the different cohorts might be related to patient survival. We used overall survival data from Cohort 1 and Cohort 2 and stratified patients by their predicted patterns of pathway activation. A primary GC profile was defined as showing high activation level of a pathway when the activation score was above zero – i.e. being positively associated with the pathway signature. Patient groups stratified by either the proliferation/stem cell pathway activation score alone or the NF-κB pathway activation score alone did not differ significantly regarding their overall survival (p>0.05 for proliferation/stem cell and NF-κB in both cohorts, Figure 5A and 5B). However, when the pathway activation scores were combined, patients with high activation levels of both NF-κB and proliferation/stem cell pathways had significantly shorter survival compared to patients with low activation levels of both NF-κB and proliferation/stem cell pathways (p = 0.0399 and p = 0.0109 for Cohorts 1 and 2 respectively, Figure 5D).

Bottom Line: We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers.Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior.Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups.

View Article: PubMed Central - PubMed

Affiliation: Duke-NUS Graduate Medical School, Singapore.

ABSTRACT
Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.

Show MeSH
Related in: MedlinePlus