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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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Patterns of pathway activation in gastric cancer cell lines.Twenty gene expression signatures representing 11 cancer-related pathways (previously described in Figure 2) were queried against a panel of 25 gastric cancer cell lines. The heatmap depicts the activation scores of pathways represented by the signatures (rows) in individual cell lines (columns), with red squares denoting higher activation scores. Pathways and cell lines were ordered using unsupervised hierarchical clustering. Similar to primary tumors, pathways related to proliferation or stem cell form a distinct cluster (brown) from other pathways (grey). Cell lines with high predicted activation of NF-κB, Wnt/β-catenin, or proliferation/stem cell-related pathways are indicated by relevant color bars at the bottom of the heatmap. For the proliferation/stem cell-related signatures, the cell lines were mean-normalized relative to one another against the mean activation score, as all cell lines scored positive for proliferation/stem cell-related pathways.
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pgen-1000676-g003: Patterns of pathway activation in gastric cancer cell lines.Twenty gene expression signatures representing 11 cancer-related pathways (previously described in Figure 2) were queried against a panel of 25 gastric cancer cell lines. The heatmap depicts the activation scores of pathways represented by the signatures (rows) in individual cell lines (columns), with red squares denoting higher activation scores. Pathways and cell lines were ordered using unsupervised hierarchical clustering. Similar to primary tumors, pathways related to proliferation or stem cell form a distinct cluster (brown) from other pathways (grey). Cell lines with high predicted activation of NF-κB, Wnt/β-catenin, or proliferation/stem cell-related pathways are indicated by relevant color bars at the bottom of the heatmap. For the proliferation/stem cell-related signatures, the cell lines were mean-normalized relative to one another against the mean activation score, as all cell lines scored positive for proliferation/stem cell-related pathways.

Mentions: To experimentally validate these primary GC pathway predictions, we applied the pathway prediction algorithm to a panel of 25 GC cell lines (GCCLs) (Figure 3). Similar to primary GC, ‘proliferation/stem cell’ and ‘oncogenic signaling’ pathway clusters were also observed in the GCCLs. Furthermore, signatures representing the same pathway, but obtained from different studies, such as the two independent MYC-derived signatures [9],[24] also clustered together in the GC cell lines after unsupervised hierarchical clustering (purple brackets in Figure 3). Guided by the pathway predictions, we identified specific GC cell lines exhibiting patterns of oncogenic pathway activity mirroring primary GCs. Confidence in the selection of specific cell lines as in vitro models was also achieved by repeating the prediction procedure seven times using a variety of reference profiles, ranging from the median GCCL profile to independent profiles such as non-malignant normal stomach profiles (see Materials and Methods and Table S4). Pairwise comparisons confirmed that any two reference profiles were more likely to produce concurring pathway predictions than conflicting predictions (Text S1 and Table S4). Some examples of representative lines include AZ521 and MKN28 cells, which exhibit activation of proliferation/stem cell pathways, YCC3 and AGS cells for Wnt/β-catenin pathways, and MKN1 and SNU5 cells for the NF-κB pathway.


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)

Patterns of pathway activation in gastric cancer cell lines.Twenty gene expression signatures representing 11 cancer-related pathways (previously described in Figure 2) were queried against a panel of 25 gastric cancer cell lines. The heatmap depicts the activation scores of pathways represented by the signatures (rows) in individual cell lines (columns), with red squares denoting higher activation scores. Pathways and cell lines were ordered using unsupervised hierarchical clustering. Similar to primary tumors, pathways related to proliferation or stem cell form a distinct cluster (brown) from other pathways (grey). Cell lines with high predicted activation of NF-κB, Wnt/β-catenin, or proliferation/stem cell-related pathways are indicated by relevant color bars at the bottom of the heatmap. For the proliferation/stem cell-related signatures, the cell lines were mean-normalized relative to one another against the mean activation score, as all cell lines scored positive for proliferation/stem cell-related pathways.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2748685&req=5

pgen-1000676-g003: Patterns of pathway activation in gastric cancer cell lines.Twenty gene expression signatures representing 11 cancer-related pathways (previously described in Figure 2) were queried against a panel of 25 gastric cancer cell lines. The heatmap depicts the activation scores of pathways represented by the signatures (rows) in individual cell lines (columns), with red squares denoting higher activation scores. Pathways and cell lines were ordered using unsupervised hierarchical clustering. Similar to primary tumors, pathways related to proliferation or stem cell form a distinct cluster (brown) from other pathways (grey). Cell lines with high predicted activation of NF-κB, Wnt/β-catenin, or proliferation/stem cell-related pathways are indicated by relevant color bars at the bottom of the heatmap. For the proliferation/stem cell-related signatures, the cell lines were mean-normalized relative to one another against the mean activation score, as all cell lines scored positive for proliferation/stem cell-related pathways.
Mentions: To experimentally validate these primary GC pathway predictions, we applied the pathway prediction algorithm to a panel of 25 GC cell lines (GCCLs) (Figure 3). Similar to primary GC, ‘proliferation/stem cell’ and ‘oncogenic signaling’ pathway clusters were also observed in the GCCLs. Furthermore, signatures representing the same pathway, but obtained from different studies, such as the two independent MYC-derived signatures [9],[24] also clustered together in the GC cell lines after unsupervised hierarchical clustering (purple brackets in Figure 3). Guided by the pathway predictions, we identified specific GC cell lines exhibiting patterns of oncogenic pathway activity mirroring primary GCs. Confidence in the selection of specific cell lines as in vitro models was also achieved by repeating the prediction procedure seven times using a variety of reference profiles, ranging from the median GCCL profile to independent profiles such as non-malignant normal stomach profiles (see Materials and Methods and Table S4). Pairwise comparisons confirmed that any two reference profiles were more likely to produce concurring pathway predictions than conflicting predictions (Text S1 and Table S4). Some examples of representative lines include AZ521 and MKN28 cells, which exhibit activation of proliferation/stem cell pathways, YCC3 and AGS cells for Wnt/β-catenin pathways, and MKN1 and SNU5 cells for the NF-κB pathway.

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