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Supplementary Materials for: Correlation between gene variants, signaling pathways and efficacy of chemotherapy drugs against colon cancers Swarnendu Tripathi,1,2,3,* Louiza Belkacemi,1 Margaret S. Cheung,2,3 and Rathindra N. Bose1 1 Departments of Biology and Biochemistry, University of Houston, Houston Texas, USA. 2Department of Physics, University of Houston, Houston Texas, USA. 3Center for Theoretical Biological Physics, Rice University, Houston Texas, USA. * Corresponding author: [email protected] Figure S1. Venn diagram of the 188 unique genes for which the mutations were analyzed across the NCI-60 colon cancer cell lines. The number of genes is indicated inside the brackets for different categories. Figure S2. GI50 data set and mean graph of PT-112 (NSC # 756765), as obtained from the NCI Development Therapeutics Program. Note that the GI50 data, only for the NCI-60 cell lines were used to calculate the z-scores of PT-112 in Figure S3. Table S1. Relevant information on the NCI-60 colon cancer cell lines as obtained from the catalogue of somatic mutation (COSMIC) (http://cancer.sanger.ac.uk/cell_lines/cbrowse/nci). Cell lines COLO_205 HCC2998 HCT_116 HCT_15 HT_29 KM12 SW620 Primary site Large Large Large Large Large Large Large (Subtype1) Intestine Intestine Intestine Intestine Intestine Intestine Intestine (Colon) (Colon) (Colon) (Colon) (Colon) (Colon) (Colon) 137 5079 1602 4766 262 1088 241 Number of mutations Figure S3. Activity of platinum (Pt) based drugs (PT-112, oxaliplatin, carboplatin and cisplatin) and 5-FU across the NCI-60 cell lines for nine different cancer types. Drug activity based on the z-scores were determined from the growth inhibitory 50% (GI50) data (see Methods in the main text) across the 60 cell lines for 9 different cancer types: BR (breast); CNS (central nervous system); CO (colon); LE (leukemia); ME (melanoma); LC (lung); OV (ovarian); PR (prostate); and RE (renal) cancer. The shaded region indicates the z-scores for the seven colon cancer cell lines. Table S2. Correlation between cisplatin activity and amino-acid (AA) variants of NCI-60 colon cancer cell lines (for genes common with oxaliplatin). “X” symbol indicates that the AA variant is not correlated with drug activity. Other genes (not in common with oxaliplatin) for which the variant(s) correlate with cisplatin activity are: PI3KCA, CREBBP, FAM123B, HNF1A, NF2, and PRDM1. Genes NF1 COLO_205 KEAP1 MTOR NOTCH1 MED12 26% (G>A) P1193L 89% (G>A) P1377S HCC2998 HCT_116 HCT_15 53% (C>T) A2596V 52% (C>T) A188T HT_29 X 69% (G>A) P1581L 100% (G>C) V312L 46% (G>A) P1377S 51% (G>A) Q265* 48% (A>C) I2500M 46% (A>T) T2029S X KM12 65% (T>G) L1361R 55% (C>T) A30T 31% (G>A) P1254L SW620 Table S3. Correlation between carboplatin activity and AA-variants (colon cancer) (for genes common with oxaliplatin). “X” symbol indicates that the AA variant is not correlated with drug activity. Other genes (not in common with oxaliplatin) for which the variant(s) correlate with carboplatin activity are: ELF3 EP300; SETD2; ATRX CHEK2 SMC3; ERBB4 FLT3; PIK3CA; APC; CDH1; LIFR USP9X; BCOR CASP8 CREBBP CYLD FAM123B GNAS MED12 NF2 PRDM1 PTCH1 SMARCA4 TSHR. Genes TSHZ3 COLO_205 HCC2998 SIN3A PBRM1 48% (G>A) R710* 38% (C>T) V1267I ATR EPHA3 HCT_116 54% (C>T) A912T 45% (G>A) P862L MED12 52% (C>A) E355D 41% (A>C) Splicing KM12 X X X 53% (C>T) A2596V 52% (C>T) A188T 51% (G>A) Q265* 26% (G>A) P1193L 89% (G>A) P1377S 65% (T>G) L1361R 55% (C>T) P1254L 48% (A>C) I2500M 46% (A>T) T2029S SW620 52% (C>G) K297N 62% (G>T) M696I KEAP1 NOTCH1 HT_29 23% (C>T) R982K NF1 MTOR HCT_15 31% (G>A) P1254L 60% (G>A) P915L 100% (G>T) G1807C 69% (G>A) P1581L 100% (G>C) V312L 46% (G>A) P1377S Table S4. Summary of biological functions of the uniquely mutated genes for which the aminoacid changing variant(s) exhibits correlation with the activity of oxaliplatin or 5-FU or both for the colon cancer cell lines. The underlined genes are related with colon cancer progression from KEGG pathway (http://www.genome.jp/dbget-bin/www_bget?pathway+hsa05210). Gene Description Function Teashirt zinc finger Transcriptional regulator involved in developmental processes. symbol TSHZ3 TSHZ2 homeobox 3 Teashirt zinc finger TSHZ2 is a protein-coding gene. Diseases associated with TSHZ2 homeobox 2 include colon cancer. An important paralog of this gene is TSHZ3. This locus encodes a subunit of ATP-dependent chromatin- PBRM1 Polybromo 1 remodeling complexes. The encoded protein an integral component of complexes necessary for ligand-dependent transcriptional activation by nuclear hormone receptors. The protein is a member of the Polycomb group of proteins, which ASXL1 Additional sex combs are necessary for the maintenance of stable repression of homeotic like 1 (Drosophila) and other loci. ASXL1 mutations are a prognostic biomarker, associated with shorter overall survival.1 Drugs targeting the spliceosome are in development to inhibit cancer progression. ATR is a serine/threonine kinase that belongs to the phosphoinositide 3- kinase related protein kinases (PIKKs), particularly to ATM (ataxia telangiectasia mutated) subfamily. It ATR Ataxia telangiectasia functions to maintain genome integrity by stabilizing replication and Rad3 related forks and by regulating cell cycle progression and DNA repair. ATR has been proposed to serve as a haplo insufficient tumor suppressor in some types of cell deficiencies and its activation has been detected in most cancer chemotherapies. This gene belongs to the ephrin receptor subfamily of the EPHA3 protein-tyrosine kinase family. EphA3 may play an important EPH receptor A3 role in the development and progression of tumours, and thus become useful indicators for clinical assessment of tumour biological behaviour and prognosis in patients with colorectal carcinoma.2 It is an autosomal-dominant inherited tumor syndrome in which NF1 affected individuals are prone to the development of both benign and malignant tumors.3 Notch signaling is an evolutionarily conserved pathway that regulates critical cellular pathways and plays a key role in the development of normal tissues and cell through various effects on differentiation, proliferation, cell fate decision and stem cell NOTCH1 renewal potential. Aberrantly activated Notch signaling plays a key role in carcinogenesis and progression of human malignancy. Notch1 as prognostic predictor and therapeutic target, both of which are relevant to practice in clinical oncology.4 POLQ is a specialized DNA polymerase. POLQ has been implicated in the defense against genomic instability, in base POLQ excision repair. Retrospective studies of clinical samples show that higher levels of POLQ gene expression in colorectal cancer are correlated with poorer outcomes for patients.5 MutL homolog 1 MLH1 A molecular phenotype associated with microsatellite instability (MSI), represents a consistent feature of tumors from patients with hereditary nonpolyposis colorectal cancer.3 Ring finger protein 34 RNF43 RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. RNF43 is one of the most commonly mutated genes in colorectal.6 IDH1 KEAP1 Isocitrate Aberrant mRNA expression of IDH1 gene might be actively dehydrogenase 1 involved in the development of colon cancer.7 Kelch-like ECH- Aberrant methylation of the KEAP1 gene promoter is emerging as associated protein 1 a main mechanism of dysregulation of the NrF2 (nuclear factorerythroid 2-related factor 2) which plays a pivotal role in the cellular response to oxidative stress. KRAS V-Ki-ras2 Kirsten rat KRas is a protein that in humans is encoded by the KRAS gene. sarcoma viral oncogene KRAS is highly mutated in colon cancer. Detailed description is given in the manuscript. MECOM MDS1 and EVI1 The protein encoded by this gene is a transcriptional regulator and complex locus oncoprotein that may be involved in hematopoiesis, apoptosis, development, and cell differentiation and proliferation. MTOR Mammalian target of mTOR is frequently activated in colon cancer due to mutations in rapamycin (mTOR) the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. NCOR1 Nuclear receptor This gene encodes a protein that mediates ligand-independent corepressor 1 transcription repression of thyroid-hormone and retinoic-acid receptors by promoting chromatin condensation and preventing access of the transcription machinery. PPP2R1A Protein phosphatase 2, This gene encodes a constant regulatory subunit of protein regulatory subunit A, phosphatase 2. Protein phosphatase 2 is one of the four major alpha Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumor progression but its role in RAD21 colorectal carcinoma is unclear. Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human colon cancer. The protein encoded by this gene is a negative regulator of the cell RB1 Rinoblastoma 1 cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. This protein is a histone methyltransferase that is specific for SETD2 SET domain containing lysine-36 of histone H3, and methylation of this residue is 2 associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II SIN3A Transcription regulator The protein encoded by this gene is a transcriptional regulatory family member A protein. Structural maintenance This gene belongs to the SMC3 subfamily of SMC proteins. The of chromosomes 3 encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear SMC3 form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. This gene encodes a member of the Ser/Thr protein kinase family and the TGFB receptor subfamily. The encoded protein is a transmembrane protein that has a protein kinase domain, forms a TGFBR2 Transforming growth heterodimeric complex with another receptor protein, and binds factor, beta receptor II TGF-. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes related to cell proliferation. ARID2 AT rich interactive ARID2 is a subunit of the PBAF chromatin-remodeling complex, domain 2 which facilitates ligand-dependent transcriptional activation by nuclear receptors.8 This gene encodes a cytoplasmic protein that contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis AXIN1 Axin 1 polyposis coli, catenin beta-1, glycogen synthase kinase 3 beta, protein phosphate 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The protein encoded by this gene was identified as an interacting corepressor of BCL6, a POZ/zinc finger transcription repressor that is required for germinal center formation and may influence BCOR BCL6 corepressor apoptosis. This protein selectively interacts with the POZ domain of BCL6, but not with eight other POZ proteins. Specific class I and II histone deacetylases (HDACs) have been shown to interact with this protein, which suggests a possible link between the two classes of HDACs. The protein encoded by this gene belongs to the membrane- CARD11 Caspase recruitment associated guanylate kinase (MAGUK) family, a class of proteins domain family, member that function as molecular scaffolds for the assembly of 11 multiprotein complexes at specialized regions of the plasma membrane. CIC HNF1A Capicua transcriptional repressor HNF1 homeobox A The protein encoded by this gene is a transcription factor. The protein encoded by this gene is a member of the Janus kinase JAK3 Janus Kinase 3 (JAK) family of tyrosine kinases involved in cytokine receptormediated intracellular signal transduction. Initiation of transcription is controlled in part by a large protein assembly; the preinitiation complex. A component of this complex MED12 Mediator complex is a 1.2 MDa protein aggregate called Mediator. This Mediator subunit 12 component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates The protein encoded by this gene is a G protein-coupled receptor SMO Smoothened, frizzled that interacts with the patched protein, a receptor for hedgehog family receptor proteins. The encoded protein transduces signals to other proteins after activation by a hedgehog protein/patched protein complex. This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded TNFAIP3 Tumor necrosis factor, by this gene is a zinc finger protein and ubiqitin-editing enzyme, alpha-induced protein 3 and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein is involved in the cytokine-mediated immune and inflammatory responses. Table S5. List of driver genes that exhibit non-synonymous mutations across the NCI-60 cell lines (see Figure 1 and 2 in the Main text). Signaling pathways/ Cellular Process Transcription factor/regulator Histone modifier Genome integrity RTK signaling Cell cycle MAPK signaling PI(3)K signaling TGF-β signaling Driver genes VHL GATA3 EP300 RUNX1 WT1 PHF6 SOX9 MLL3 ARID1A PBRM1 SETD2 SETBP1 KDM5C KDM6A ASXL1 EZH2 TP53 ATM ATRX BRCA2 STAG2 BAP1 BRCA1 EGFR FLT3 PDGFRA FGFR2 FGFR3 CDKN2A RB1 KRAS NF1 MAP3K1 BRAF NRAS PIK3CA PTEN PIK3R1 SMAD4 ACVR1B SMAD2 Wnt/β -catenin signaling Proteolysis Splicing HIPPO signaling DNA methylation Metabolism NFE2L Protein phosphatase Other Cell survival APC CTNNB1 FBXW7 SPOP SF3B1 U2AF1 CDH1 DNMT3A TET2 IDH1 NFE2L2 PPP2R1A PTPN11 NOTCH1 NCOR1 AR ABL1 ALK B2M CARD11 CASP8 CBL CDC73 CIC CSF1R CYLD ERBB2 GNA11 GNAQ GNAS HRAS JAK1 JAK2 JAK3 MAP2K1 MED12 MET MPL MYD88 RET SOCS1 TNFAIP3 TRAF7 TSC1 TSHR Cell fate Genome maintanence ARID1B ARID2 AXIN1 BCOR CREBBP DNMT1 FAM123B GATA1 GATA2 HNF1A KLF4 MEN1 NF2 NOTCH2 PAX5 PRDM1 PTCH1 RNF43 SMARCA4 SMARCB1 SMO MLH1 MSH2 MSH6 REFERENCES 1 2 3 4 5 6 7 8 Bejar, R. et al. 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