Urvival than the rest from the individuals (determined by log-rank test

Urvival than the rest in the patients (based on log-rank test, P 0.012). The prognostic impact is preserved in theNATURE COMMUNICATIONS | 7:12991 | DOI: ten.1038/ncomms12991 | www.nature.com/naturecommunicationsNATURE COMMUNICATIONS | DOI: 10.1038/ncommsARTICLECandidate targetsaxi nibSpearman correlation (R )1 0.9 0.8 0.7 0.6 0.5Concept DbInteractomeCopy number Human genome Regularly amplified1 kPathways Gene OntologiesRNAseq exp Rankings Expression correlated Druggability Functionally importantOntology term bOntology term c….DomainsConSig AnalysisMYC EGFR CCNDMotifs….cChr17q23.Chr17: 57,000-59,000 kbTLK2 expression (log2) (RNAseq)TLK2 expression(log2)(RNAseq)TCGA breast cancer tumor/blood pairs1.5 0 .Tumor BloodBasal Her2 LumA LumBWt MutTLKI II III IV Stage P53 PIK3CAf1 Probability of survival 0.eight 0.6 0.4 0.two 0 YearER+, n =626 1 0.8 0.6 0.four Higher TLK2 Rest OS: P =0.040 two four 6 eight 10 TCGA RNAseq expression data 0.2 0ER+/Tam, n =263 1 0.8 0.6 0.four High TLK2 Rest RFS: P=0.001 four six eight ten Loi et al. JCO. 2007 (Ref 20) two 0.two 0ER+/Unt, n=219 1 0.8 0.six 0.4 High TLK2 Rest DSS: P=0.012 two four 6 eight 10 0.ER+/HT, n=High TLK2 Rest0 DSS: P=0.012 0 4 6 8 ten Curtis et al. Nature 2012 (Ref 18)Curtis et al. Nature 2012 (Ref 18)Figure 1 | ConSig-Amp identifies TLK2 as a candidate druggable target often amplified in breast cancer. (a) The bioinformatics workflow of ConSig-Amp to uncover therapeutically relevant oncogene targets in cancer at genome-wide scale based on copy-number and RNAseq information sets. The ConSig-Amp score is calculated by multiplying the ConSig score (see Procedures) with the correlation involving gene expression and copy number. (b) Prioritizing amplified breast cancer oncogene targets by ConSig score and Spearman’s correlation among copy number (Affymetrix SNP 6.Cathepsin S Protein Formulation 0 array) and gene expression (RNAseq). Data shown here are from TCGA. (c) Representative copy-number data showing amplifications at the TLK2 locus in paired breast tumour and peripheral blood (information from TCGA52), or breast cancer cell lines (data from Heiser et al.21). This figure is based on Affymetrix SNP six.0 array data annotated with genome develop hg18. Constructive cell line or tumour samples are sorted according to the amount of TLK2 amplifications, along with the structures of genes involved inside the presented region are shown beneath the illustration. (d) TLK2 expression (depending on RNAseq data) is primarily regulated by gene copy number (determined by Affymetrix SNP six.0 array information). The Spearman’s correlation is R 0.81. (e) TLK2 expression in various breast cancer subtypes based on RNAseq data.VHL Protein supplier Copy number and RNAseq expression information shown in d,e are from TCGA.PMID:24856309 The whiskers indicate the max and min values (excluding outliers) and horizontal lines represent the 1st, 2nd and 3rd quartiles. *Po0.05; ***Po0.001. (f) Kaplan eier plots depending on a number of gene expression data sets showing correlation of TLK2 overexpression together with the outcome of systemically untreated or endocrine-treated ER breast cancer patients. HT, hormone treated; Tam, tamoxifen-treated; Unt, untreated. P values are calculated depending on log-rank tests.389 ER breast cancer individuals treated with endocrine monotherapy (according to log-rank test, P 0.012). Of note, about 93 in the untreated and endocrine-treated ER tumours in the Metabric information set are Her2 unfavorable. These information help a poorer outcome of individuals with TLK2-high tumours irrespective of endocrine therapy.NATURE COMMUNICATIONS | 7:12991 | DOI: 10.1038/ncomms12991 | www.nature.com/natu.