EGAGenomicsIllumina HiSeq 2000, Illumina_2.5MCancer Genomicshttps://ega-archive.org/studies/EGAS00001000288EGAEGA study EGAS00001000288RNA sequencing of colon tumor/normal sample pairsTitle not providedWhole genome sequencing of colon samplesExome capture sequencing of colon tumor/normal pairsrestrictedEGAIdentifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.Recurrent R-spondin fusions in colon cancer.Seshagiri Somasekar S, Stawiski Eric W EW, Durinck Steffen S, Modrusan Zora Z, Storm Elaine E EE, Conboy Caitlin B CB, Chaudhuri Subhra S, Guan Yinghui Y, Janakiraman Vasantharajan V, Jaiswal Bijay S BS, Guillory Joseph J, Ha Connie C, Dijkgraaf Gerrit J P GJ, Stinson Jeremy J, Gnad Florian F, Huntley Melanie A MA, Degenhardt Jeremiah D JD, Haverty Peter M PM, Bourgon Richard R, Wang Weiru W, Koeppen Hartmut H, Gentleman Robert R, Starr Timothy K TK, Zhang Zemin Z, Largaespada David A DA, Wu Thomas D TD, de Sauvage Frederic J FJAdenocarcinoma, colon tumor, Colon Neoplasm, Colon Cancers, malignant neoplasm of colon, Colonic, Colon Adenocarcinomas, malignant, Neoplasms, susceptibility to, Colonic Neoplasm, Colon cancer, Colonic Cancer, Colon Cancer, Cancers, Cancer of the Colon, Colon Adenocarcinoma, Colon, Adenocarcinomas, autosomal dominant, large intestine cancer, colon neoplasm, malignant colon tumor, malignant colonic tumour, malignant colonic neoplasm, malignant colon tumour., Colonic Cancers, colon cancer, Cancer of Colon, malignant tumour of the colon, malignant neoplasm of the colon, Neoplasm, Colon Neoplasms, malignant tumor of colon, malignant colonic tumor, malignant tumour of colon, CRC, cancer of colon, malignant colon neoplasm, somatic mutation, malignant tumor of the colon, CancerErbb-3, Dm DWnt3/5, para Tyrosine, DWnt-5, DWnt-4, Materials, Kinship, malignant neoplasm of colon, mTcf-4B, mTcf-4E, tef, l(2)wg, growth and development, Colon Cancer, Tumor, Cristin1, Mutations, ErbB-3, malignant colonic neoplasm, wnt-4, atm/tefu, RSPO, int-1, Dm-1, Appendix, Dm-2, Ayu17-449, Dm-3, DmelCG1916, Life Cycle, malignant tumor of colon, Analysis, TCF4E, CG1451, TCF4B, Thsd2, Kinship Network, I, Igf-II, Genomes, Analyses, cell process disease, tumor disease, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Y, WNT, Wnt, SURGICAL AND MEDICAL PROCEDURES, AI047805, Role Concepts, telo1, Br, dWnt2, cancer of colon, wnt, single organism signaling, Tumors, din, para-Tyrosine, Procedure, Appendix Epiploica, p85-sErbB3, tumours, d-APC, APC2, Apc1, APC1, LCCS2, Benign, Role Concept, E-APC dAPC2, D-wnt-2, apc 1, XTCF-4, tetraspanin3, apc1, Role, tetraspanin2, apc2, Omental Appendices, CG4889, activation, RGD1563246, fg, Benign Neoplasms, INSDC_feature:gene, Colon, Dm APC2, human, Dm APC1, Malignant Neoplasms, L isomer, AL033362, PP1446, COLON, Material, GS, L-Tyrosine, other neoplasm, Adenocarcinoma, D-Axin, e-apc, Neoplasms, number, protein-containing complex, Erbb3r, NEOPL, Human, DmelCG6535, DP3, DP2, insigf, Core Genome, Gene Products, C11orf43, malignant tumour of colon, neoplasm, Man, DmelCG6407, interventionDescription, Accessory Genome, E130014J05Rik, posterior intestine, tumour, dWnt, CG7926, Neoplasias, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), malignant colonic tumour, Wnt3/5, dAPC2/E-APC, DmelCG4698, M6pr, D430027K22, Tyrosin, Neoplastic Growth, Cancer, RGD1562331, Malignant Neoplasm, Family Research, l(2)rO727, Proteins, KIAA1546, CG6535, Pangenome, hindgut, MDS, Concept, Family Members, neoplastic growth, Peg2, spd, MT, native protein, tirosina, chemical analysis, Neoplasm, p45-sErbB3, CRC, d-APC2, Intervention, AU020952, AI256621, C76256, Colon Cancers, primary cancer, c-erbB3, THSD2, CHK1 checkpoint homolog, CG4698, postnatal growth, Colonic Neoplasm, Cancers, Omental, Understanding, 2810459H04Rik, disease of cellular proliferation, malignant tumor, DAxin, signalling, Gene Proteins, Pan-genome, colon cancer, signalling process, Families, DmelCG7926, F3P11.18, APC, DWnt-3, DWnt-2, DWnt-1, Relatives, Neoplasia, NEOPLASMS BENIGN, Data Analyses, F3P11_18, CG6407, Networks, D-APC1, D-APC2, single-organism developmental process, determination, Dint-1, DmelCG4889, Daxin, neoplasia, postnatal development, apc, protein, igf2, Readability, PPP1R46, d-axin, Roles, Taenia Coli, MDA-BF-1, IGFII, Concepts, Min, GSK3beta, Dm Wg, protein aggregate, Wnt-4, l(2)02657, Wnt-1, Chromatins, malignant tumor of the colon, TELO1, Wnt-3, Family Life Cycle, Wnt-2, Omental Appendix, Man (Taxonomy), mKIAA1546, neoplasm (disease), mAPC, Colonic Cancer, tcf4e, DWnt5, RGD1311625, DWnt4, DWnt3, DWnt2, AT1, large intestine cancer, at1, AA673245, malignant neoplasm, Dwnt5, Tyr, signaling process, Dwnt4, erbB3-S, chromosome scaffold, ATA, malignant neoplasm of the colon, cyclosome, Therapies, ATC, ATD, ATE, Malignancies, tumor, Family Life Cycles, ATM, Atm, somatic mutation, Sp, nuclear chromatin, Therapy, DmelCG1451, dApc2, l(3)S044230, DP2.5, Modern, 2-Amino-3-(p-hydroxyphenyl)propionic acid, RNA-seq, neoplastic disease, Colon Adenocarcinoma, atm, Adenocarcinomas, pp9974, Tyrosine, 2610028F08Rik, malignant colon tumour., xapc, Colonic Cancers, clone 2.4, Genetic Materials, malignant colonic tumor, DWint-1, Igf-2, Filiation, Genetic Material, dAPC2, dAPC1, IGF-II, DWnt3/5, B430006D22Rik, R-spondin, CRISTIN1, anon-WO03040301.228, CRISTIN2, CRISTIN3, anon-EST:Liang-2.4, susceptibility to, WG, L-isomer, 0442/30, Exomes, Appendices, AW124434, Treatments, ATATM, RNIGF2, PWTSR, Life Cycles, data analysis, CG1916, ftls, Cancer of Colon, Wg, Cistron, PP9974, anaphase promoting complex, malignant colon neoplasm, colon tumor, Colon Neoplasm, cytoplasmic chromatin, biological signaling, human being, Tefu, Family Member, tcf4, ARABIDOPSIS THALIANA ATAXIA-TELANGIECTASIA MUTATED, Colon Adenocarcinomas, Mpr, Benign Neoplasm, Gene, axn, Network, Malignant, presence, autosomal dominant, DWnt-3/5, BC037432, Intervention or Procedure, TCF-4, colon neoplasm, AW742308, Homo sapiens, C030026E19Rik, DAPC, CG6193, Colon Neoplasms, Whole Transcriptome Shotgun Sequencing, BTPS2, D-APC, dApc, dAPC, tel1, study, Genetic, Colonic, Malignancy, Research, Tcf-4, Interventional, Cancer of the Colon, igf-2, Wnt/Wg, Wnt1, Wnt3, wnt4, wnt3, wnt2, malignant colon tumor, wnt1, Checkpoint kinase-1, data processing, L Tyrosine, Xatm, wnt5, Kinship Networks, Family, Tcf4, TCF4, DmelCG6193, Rspondin, dAxin, Intervention Strategies, protein complex, E-APC, malignant, Cistrons, wgl, dAXIN, p180-ErbB3, development, count in organism, 2.7.11.1, Protein, nuc-ErbB3, TEL1, axin, dATM, c-erbB-3, CC1, Colon cancer, Dwnt-2, Dwnt-3, ataxia-telangiectasia mutated, Dm DWnt2, Dm DWnt4, atdc, Protein Gene Products, Therapeutic, Data, Dwnt-5, ATDC, Modern Man, Cell cycle checkpoint kinase, malignant tumour of the colon, cardinality, Treatment, assay, D230004J03Rik, growth, Her3, Gla, HER3Rspondin, Adenocarcinoma, colon tumor, Colon Neoplasm, Colon Cancers, malignant neoplasm of colon, Colonic, R-spondin, Colon Adenocarcinomas, malignant, Neoplasms, susceptibility to, Colonic Neoplasm, Colon cancer, Colonic Cancer, Colon Cancer, Cancers, Cancer of the Colon, Colon Adenocarcinoma, Colon, Adenocarcinomas, autosomal dominant, large intestine cancer, colon neoplasm, malignant colon tumor, malignant colonic tumour, malignant colonic neoplasm, malignant colon tumour., Colonic Cancers, colon cancer, Cancer of Colon, malignant tumour of the colon, malignant neoplasm of the colon, Neoplasm, Colon Neoplasms, malignant tumor of colon, malignant colonic tumor, malignant tumour of colon, CRC, cancer of colon, malignant colon neoplasm, somatic mutation, malignant tumor of the colon, CancerErbb-3, Dm DWnt3/5, para Tyrosine, DWnt-5, DWnt-4, Materials, Kinship, malignant neoplasm of colon, mTcf-4B, mTcf-4E, tef, l(2)wg, growth and development, Colon Cancer, Tumor, Cristin1, Mutations, ErbB-3, malignant colonic neoplasm, wnt-4, atm/tefu, RSPO, int-1, Dm-1, Appendix, Dm-2, Ayu17-449, Dm-3, DmelCG1916, Life Cycle, malignant tumor of colon, Analysis, TCF4E, CG1451, TCF4B, Thsd2, Kinship Network, I, Igf-II, Genomes, Analyses, cell process disease, tumor disease, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Y, WNT, Wnt, SURGICAL AND MEDICAL PROCEDURES, AI047805, Role Concepts, telo1, Br, dWnt2, cancer of colon, wnt, single organism signaling, Tumors, din, para-Tyrosine, Procedure, Appendix Epiploica, p85-sErbB3, tumours, d-APC, APC2, Apc1, APC1, LCCS2, Benign, Role Concept, E-APC dAPC2, D-wnt-2, apc 1, XTCF-4, tetraspanin3, apc1, Role, tetraspanin2, apc2, Omental Appendices, CG4889, activation, RGD1563246, fg, Benign Neoplasms, INSDC_feature:gene, Colon, Dm APC2, human, Dm APC1, Malignant Neoplasms, L isomer, AL033362, PP1446, COLON, Material, GS, L-Tyrosine, other neoplasm, Adenocarcinoma, D-Axin, e-apc, Neoplasms, number, protein-containing complex, Erbb3r, NEOPL, Human, DmelCG6535, DP3, DP2, insigf, Core Genome, Gene Products, C11orf43, malignant tumour of colon, neoplasm, Man, DmelCG6407, interventionDescription, Accessory Genome, E130014J05Rik, posterior intestine, tumour, dWnt, CG7926, Neoplasias, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), malignant colonic tumour, Wnt3/5, dAPC2/E-APC, DmelCG4698, M6pr, D430027K22, Tyrosin, Neoplastic Growth, Cancer, RGD1562331, Malignant Neoplasm, Family Research, l(2)rO727, Proteins, KIAA1546, CG6535, Pangenome, hindgut, MDS, Concept, Family Members, neoplastic growth, Peg2, spd, MT, native protein, tirosina, chemical analysis, Neoplasm, p45-sErbB3, CRC, d-APC2, Intervention, AU020952, AI256621, C76256, Colon Cancers, primary cancer, c-erbB3, THSD2, CHK1 checkpoint homolog, CG4698, postnatal growth, Colonic Neoplasm, Cancers, Omental, Understanding, 2810459H04Rik, disease of cellular proliferation, malignant tumor, DAxin, signalling, Gene Proteins, Pan-genome, colon cancer, signalling process, Families, DmelCG7926, F3P11.18, APC, DWnt-3, DWnt-2, DWnt-1, Relatives, Neoplasia, NEOPLASMS BENIGN, Data Analyses, F3P11_18, CG6407, Networks, D-APC1, D-APC2, single-organism developmental process, determination, Dint-1, DmelCG4889, Daxin, neoplasia, postnatal development, apc, protein, igf2, Readability, PPP1R46, d-axin, Roles, Taenia Coli, MDA-BF-1, IGFII, Concepts, Min, GSK3beta, Dm Wg, protein aggregate, Wnt-4, l(2)02657, Wnt-1, Chromatins, malignant tumor of the colon, TELO1, Wnt-3, Family Life Cycle, Wnt-2, Omental Appendix, Man (Taxonomy), mKIAA1546, neoplasm (disease), mAPC, Colonic Cancer, tcf4e, DWnt5, RGD1311625, DWnt4, DWnt3, DWnt2, AT1, large intestine cancer, at1, AA673245, malignant neoplasm, Dwnt5, Tyr, signaling process, Dwnt4, erbB3-S, chromosome scaffold, ATA, malignant neoplasm of the colon, cyclosome, Therapies, ATC, ATD, ATE, Malignancies, tumor, Family Life Cycles, ATM, Atm, somatic mutation, Sp, nuclear chromatin, Therapy, DmelCG1451, dApc2, l(3)S044230, DP2.5, Modern, 2-Amino-3-(p-hydroxyphenyl)propionic acid, RNA-seq, neoplastic disease, Colon Adenocarcinoma, atm, Adenocarcinomas, pp9974, Tyrosine, 2610028F08Rik, malignant colon tumour., xapc, Colonic Cancers, clone 2.4, Genetic Materials, malignant colonic tumor, DWint-1, Igf-2, Filiation, Genetic Material, dAPC2, dAPC1, IGF-II, DWnt3/5, B430006D22Rik, R-spondin, CRISTIN1, anon-WO03040301.228, CRISTIN2, CRISTIN3, anon-EST:Liang-2.4, susceptibility to, WG, L-isomer, 0442/30, Exomes, Appendices, AW124434, Treatments, ATATM, RNIGF2, PWTSR, Life Cycles, data analysis, CG1916, ftls, Cancer of Colon, Wg, Cistron, PP9974, anaphase promoting complex, malignant colon neoplasm, colon tumor, Colon Neoplasm, cytoplasmic chromatin, biological signaling, human being, Tefu, Family Member, tcf4, ARABIDOPSIS THALIANA ATAXIA-TELANGIECTASIA MUTATED, Colon Adenocarcinomas, Mpr, Benign Neoplasm, Gene, axn, Network, Malignant, presence, autosomal dominant, DWnt-3/5, BC037432, Intervention or Procedure, TCF-4, colon neoplasm, AW742308, Homo sapiens, C030026E19Rik, DAPC, CG6193, Colon Neoplasms, Whole Transcriptome Shotgun Sequencing, BTPS2, D-APC, dApc, dAPC, tel1, study, Genetic, Colonic, Malignancy, Research, Tcf-4, Interventional, Cancer of the Colon, igf-2, Wnt/Wg, Wnt1, Wnt3, wnt4, wnt3, wnt2, malignant colon tumor, wnt1, Checkpoint kinase-1, data processing, L Tyrosine, Xatm, wnt5, Kinship Networks, Family, Tcf4, TCF4, DmelCG6193, Rspondin, dAxin, Intervention Strategies, protein complex, E-APC, malignant, Cistrons, wgl, dAXIN, p180-ErbB3, development, count in organism, 2.7.11.1, Protein, nuc-ErbB3, TEL1, axin, dATM, c-erbB-3, CC1, Colon cancer, Dwnt-2, Dwnt-3, ataxia-telangiectasia mutated, Dm DWnt2, Dm DWnt4, atdc, Protein Gene Products, Therapeutic, Data, Dwnt-5, ATDC, Modern Man, Cell cycle checkpoint kinase, malignant tumour of the colon, cardinality, Treatment, assay, D230004J03Rik, growth, Her3, Gla, HER3falseGenentech Colon Cancer ScreenIdentifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.2019-10-31 12:52:09EGAS00001000288960622895193EGAD00010000274EGAD00001000216EGAD00001000215EGAD00001000214EGAD00010000272EGAC00001000055