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. 2009 Jun;87(6):633-44.
doi: 10.1007/s00109-009-0467-y. Epub 2009 Apr 28.

An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types

Eike Staub  1 , Joern Groene, Maya Heinze, Detlev Mennerich, Stefan Roepcke, Irina Klaman, Bernd Hinzmann, Esmeralda Castanos-Velez, Christian Pilarsky, Benno Mann, Thomas Brümmendorf, Birgit Weber, Heinz-Johannes Buhr, André Rosenthal
Affiliations

An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types

Eike Staub et al. J Mol Med (Berl). 2009 Jun.

Abstract

Wiskott-Aldrich syndrome (WAS) predisposes patients to leukemia and lymphoma. WAS is caused by mutations in the protein WASP which impair its interaction with the WIPF1 protein. Here, we aim to identify a module of WIPF1-coexpressed genes and to assess its use as a prognostic signature for colorectal cancer, glioma, and breast cancer patients. Two public colorectal cancer microarray data sets were used for discovery and validation of the WIPF1 co-expression module. Based on expression of the WIPF1 signature, we classified more than 400 additional tumors with microarray data from our own experiments or from publicly available data sets according to their WIPF1 signature expression. This allowed us to separate patient populations for colorectal cancers, breast cancers, and gliomas for which clinical characteristics like survival times and times to relapse were analyzed. Groups of colorectal cancer, breast cancer, and glioma patients with low expression of the WIPF1 co-expression module generally had a favorable prognosis. In addition, the majority of WIPF1 signature genes are individually correlated with disease outcome in different studies. Literature gene network analysis revealed that among WIPF1 co-expressed genes known direct transcriptional targets of c-myc, ESR1 and p53 are enriched. The mean expression profile of WIPF1 signature genes is correlated with the profile of a proliferation signature. The WIPF1 signature is the first microarray-based prognostic expression signature primarily developed for colorectal cancer that is instrumental in other tumor types: low expression of the WIPF1 module is associated with better prognosis.

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Figures

Fig. 1
Fig. 1
Discovery and validation of the WIPF1 coexpression module. a The histogram shows the distribution of p values resulting from tests for correlation of the WIPF1 expression profile with expression profiles of each other gene in the Aronow data set. b The histogram shows the distribution of 430 p values resulting from correlation of expression profiles in the Ayers data set of the WIPF1 gene with each discovered gene in the Aronow data set. Note the strong deviation from the uniform distribution, indicating a high rate of successful validation. c A scatter plot of the correlation coefficients in Aronow and Ayers data of each of the 112 successfully validated genes reveals that most validated genes are positively correlated with the WIPF1 profile and only six genes are anti-correlated with WIPF1. All correlation coefficients are consistent in both data sets, i.e., they have the same sign
Fig. 2
Fig. 2
Two-way hierarchical clustering of colorectal cancer expression data from WIPF1-coexpressed genes. The data set results from fusing the Aronow and Ayers data sets and comprises 112 genes and 159 patients. Top: The dendrogram results from hierarchical clustering of tumors. Light gray indicates low expression, dark gray indicates high expression (log-transformed mean-centered). Five clusters of tumors are evident: cluster A is colored in red, all other clusters are colored in black. Left: The dendrogram results from hierarchical clustering of genes. Two main clusters of genes are evident: the larger cluster X is colored in red, the smaller cluster Y in black. Note the characteristic down-regulation of genes from cluster X in tumors from cluster A. Other tumors have anti-correlated or indifferent expression profiles
Fig. 3
Fig. 3
Differences in survival between colorectal cancer patients of the “cluster B” type in an independent microarray data set. Tumors that resembled the cluster “A” type were predicted by machine learning in an independent data set of 62 tumors with microarray expression profiles. Nine cluster “A”-like patients all survived until the study end. The difference in survival compared with 53 remaining patients is significant with p = 0.011 in the logrank test
Fig. 4
Fig. 4
The WIPF1 module identifies breast cancer and glioma patients with better prognosis. Histogram (a) visualizes the distribution of p values resulting from logrank tests for the association of profiles of single genes of the WIPF1 module with relapse in the Wang data on breast cancers. b The Kaplan–Meier curves for breast cancer patients assigned to the groups cluster “A” (upper curve) or cluster “B”. Histogram (c) visualizes the distribution of p values resulting from logrank tests for the association of single expression profiles of the WIPF1 coexpressed genes with relapse in the Phillips data on gliomas. d The Kaplan–Meier curves for glioma patients assigned to the groups “A” (upper curve) or “B”. Note the strong deviation from the uniform distribution (that would result from chance association) in plots (a) or (c) and the consistently higher fractions of survivors among “A” patients in (b) and (d). These plots visualize the high fraction of genes of the WIPF1 module that are individually associated with survival in breast and brain cancers and the survival significance of the complete module
Fig. 5
Fig. 5
Similarity of the WIPF1 and proliferation signatures. We determined average profiles (signature centroids) of the WIPF1 and the proliferation signatures in three data sets. Only 107 of 112 WIPF1 module genes with concordant lower expression in cluster X of the WIPF1 signature were considered for this analysis. Signature centroids were determined using averaging over all genes for each patient. The scatter plots visualize the strength of the correlation between proliferation signature and WIPF1 signature. Coordinates of each data point correspond to a single patient’s averaged mean-centered expression values for both signatures, a for the Staub colorectal cancer data set, b for the Wang breast cancer data set, and c for the Phillips glioma expression data set
Fig. 6
Fig. 6
Fused transcriptional regulation network of genes of the WIPF1 module that are regulated by c-myc, ESR1 or p53. Here we show the fused network of WIPF1 co-expressed genes that are linked to c-myc, ESR1 or p53 according to literature evidence. The legend on the left depicts the graphical symbols that describe the type of protein in the network. The arrows indicate the direction of the regulation. The colors of circles around gene names represent the coupling to transcription factors: green for c-myc, red for p53, blue for ESR1
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References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '10878810', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/10878810/'}]}
    2. Moreau V, Frischknecht F, Reckmann I et al (2002) A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization. Nat Cell Biol 2:441–448 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1073/pnas.94.26.14671', 'is_inner': False, 'url': 'https://doi.org/10.1073/pnas.94.26.14671'}, {'type': 'PMC', 'value': 'PMC25088', 'is_inner': False, 'url': 'https://pmc.ncbi.nlm.nih.gov/articles/PMC25088/'}, {'type': 'PubMed', 'value': '9405671', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9405671/'}]}
    2. Ramesh N, Antón IM, Hartwig JH et al (1997) WIP, a protein associated with Wiskott–Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc Natl Acad Sci U S A 94:14671–14676 - PMC - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S0092-8674(02)01076-0', 'is_inner': False, 'url': 'https://doi.org/10.1016/s0092-8674(02)01076-0'}, {'type': 'PubMed', 'value': '12437929', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/12437929/'}]}
    2. Volkman BF, Prehoda KE, Scott JA et al (2002) Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott–Aldrich Syndrome. Cell 111:565–576 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1074/jbc.M609902200', 'is_inner': False, 'url': 'https://doi.org/10.1074/jbc.m609902200'}, {'type': 'PubMed', 'value': '17229736', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/17229736/'}]}
    2. Peterson FC, Deng Q, Zettl M et al (2007) Multiple WASP-interacting protein recognition motifs are required for a functional interaction with N-WASP. J Biol Chem 282:8446–8453 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/path.2088', 'is_inner': False, 'url': 'https://doi.org/10.1002/path.2088'}, {'type': 'PubMed', 'value': '17086554', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/17086554/'}]}
    2. Curcio C, Pannellini T, Lanzardo S et al (2007) WIP null mice display a progressive immunological disorder that resembles Wiskott–Aldrich syndrome. J Pathol 211:67–75 - PubMed

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