EGAGenomicsAB SOLiD System 3.0;https://ega-archive.org/datasets/EGAD0000100020128EGA dataset EGAD00001000201EGAEndometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.Liang Han H, Cheung Lydia W T LW, Li Jie J, Ju Zhenlin Z, Yu Shuangxing S, Stemke-Hale Katherine K, Dogruluk Turgut T, Lu Yiling Y, Liu Xiuping X, Gu Chao C, Guo Wei W, Scherer Steven E SE, Carter Hannah H, Westin Shannon N SN, Dyer Mary D MD, Verhaak Roeland G W RG, Zhang Fan F, Karchin Rachel R, Liu Chang-Gong CG, Lu Karen H KH, Broaddus Russell R RR, Scott Kenneth L KL, Hennessy Bryan T BT, Mills Gordon B GBVasp, VASP, Data Set., DmelCG15112, ENHANCER OF ATNSI ACTIVITY, MENA, NDPP1, l(2)02029, Enb, enb, ENA, Ena, CG15112, ENA/VASPEndometrial Cancer, Carcinoma, Endometrial Carcinoma., Genomics, Complete Exome Sequencings, Complete Exome, Comparative, Neoplasms, Exome, Gene, Functional Genomics, endometrial neoplasm, Neoplasm Genes, malignant endometrial neoplasm, Exome Sequencing, malignant neoplasm of endometrium, Structural, tumor of Endometrium, primary malignant neoplasm of endometrium, Functional, Neoplasm, endometrial Ca, Whole Transcriptome, Transcriptome Sequencing, endometrial cancer, Endometrial Neoplasm, Carcinomas, WES, Complete Transcriptome, tumour of endometrium, Endometrial cancer, Complete, Genes, Cancer of the Endometrium, Complete Transcriptome Sequencing, Exome Sequencings, Endometrium Carcinomas, Endometrial Carcinomas, Endometrium Cancers, Complete Exome Sequencing, Comparative Genomics, Whole Transcriptome Sequencing, Cancers, Cancer Gene, Endometrium Cancer, Endometrial Cancers, Sequencing, Endometrium, Neoplasm Gene, ENDMC, neoplasm of endometrium, Endometrial, Whole Exome, Cancer Genes, Endometrium Carcinoma, Whole, Whole Exome Sequencing, Cancer of Endometrium, tumor of endometrium, Structural Genomics, Transcriptome Sequencings, Carcinoma of Endometrium, CancerAI662476, AI528660, mandaselin, Endometriosis, MANEA, D-endo, DmelCG14296, D-endoA, Dendo-A, endo-alpha mannosidase, S-endoglin, Endo, CD105, endomannosidase, endo, CG14296.Erbb-3, PRKBA, Akt/PKB, S6PKh1, Materials, dP60, fts-B, Vps34, DAKT1/PKB, A4, BcDNA:LD15217, Tumor, Biological Assay, AKT1, VPS34, 11621, phosphorylation, P270, Mutations, 5730420M11Rik, ErbB-3, PI-3 kinase, Repeat Associated siRNA, p110-alpha, Small, Bio Informatics, Line, High-Throughput Screening, Whole Transcriptome, Transcriptome Sequencing, High-Throughput Chemical Assays, Kinase, HWNT11, average, gamma sarcoglycan, S6K-delta-1, SET, Dp60, PI3K_59F, sensory organ, PI3-kinase activity, PI3Kgamma, Computational, RacPK, DmelCG4299, ENDMC, allergic reaction, MCAP, set, Transforming Genes, Repeat-Associated, PI3K 68D, Cancer of Endometrium, Homo sapiens disease, Screening Assay, Computational Molecular Biologies, ELD, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, Tumors, hOSA1, dVps34, rea, Exome, Biologies, 2310009M18Rik, CORD19, p50alpha, High Throughput Chemical Assays, p85-sErbB3, CG2699, Computational Molecular, DmelCG5373, Short, IBP3, GC79, AKT/PKB, LCCS2, Benign, C530050K14, tumor of Endometrium, Computational Molecular Biology, type-1 PI3K, primary malignant neoplasm of endometrium, High-Throughput Chemical, p-Akt, sarcoglycan, activation, Carcinomas, CG11621, Complete Transcriptome, HLA-DR-associated protein II, DI-2, I-2Dm, Osa1, OSA1, Phosphoinositide 3 Kinase, Benign Neoplasms, organ of sense organ system, Cancer Gene, Repeat Associated, dAKT/dPKB, PKB/dAKT, DmelCG4141, F8A5_4, Malignant Neoplasms, I-2PP1, APDS, Oncogene, TAF-IBETA, Material, 35kD dystrophin-associated glycoprotein, PI3KBETA, Ft, Whole Exome Sequencing, TAF-Ibeta, other neoplasm, RAC-ALPHA, Ft1, mKIAA0998, DmelCG4006, FRP, Phosphatidylinositol 3 Kinase, D15Ertd586e, Peptidomics, Neoplasms, PYKL, Phosphoinositide 3, endometrial neoplasm, Erbb3r, FT1, GPRC1H, PIK3, dVps34/PI3K59F, Pi3Kp60, sensitive, High-Throughput Biological, PI3K-dp110, High-Throughput Screening Assay, Small Scan RNA, disease or disorder, Screening, dPI3K, anon-92Ed, MAM, gamma-SG, Medical, class I, Endometrial cancer, scnRNA, FTS, Fts, B130003F20Rik, Complete, Exome Sequencings, Transforming Gene, Clinical, High Throughput Screening Methods, BAF250, PHK, Phk, 2pp2a, Pi3Kp110, RPK118, CG10574, Sequencing, Short Hairpin, P110BETA, Neoplasias, neoplasm of endometrium, Endometrial, High Throughput Screening Assays, 1700048H13Rik, fts, Whole Exome, 2PP2A, PI3K21B, AKT, Akt, Whole, Trans Acting siRNA, dSET, dSet, sensillum, MCM, MGLUR8, tasiRNA, Cancer, Cpk, RNA, Trans-Acting, SMARCF1, Malignant Neoplasm, Complete Exome Sequencings, BM029, AA414921, 35 kDa dystrophin-associated glycoprotein, akt, Screening Method, class II, type III phosphoinositide 3-kinase activity, Assay, disorders, Phosphorylations, shRNA, DAkt1, DAKT1, Cell, PI(3)K, SGCG, Small Hairpin RNA, cpk, Short Interfering, PI3K-92E/Dp110, malignant endometrial neoplasm, Exome Sequencing, PIK3C1, RSKL1, PKB, MT, CWS6, CWS5, I-2PP2A, High Throughput Biological Assays, 6330505C01Rik, 1110030E03Rik, Dm I-2, PKB-ALPHA, Neoplasm, endometrial Ca, condition, AI649005, p45-sErbB3, CG4006, aktip, humS6PKh1, sensor, Endometrial Neoplasm, Chemical Assay, Dakt1, MRD14, C76256, Small Interfering RNA, High Throughput Screening, DMDA1, underdeveloped, ensemble, c-erbB3, Carcinogeneses, Specificity, High-Throughput Screening Methods, Cancers, DmelCG11621, caPI3K, dAkt/PKB, CLOVE, DmVps34, siRNA, IMD14, PI3K_68D, PI3K-92D, Dmp110, AI115454, General activity, Neoplasia, C80612, Repeat-Associated siRNA, Endometrial Cancer, MGC130048, IPP2A2, CG5373, Activity, ATVPS34, Glur8, AI428864, GSD9A, Small Hairpin, Smarcf1, organ of sensory system, PI3K, Dp110, Molecular Biologies, MAPKAP-K2, Neoplasm Genes, 1-Phosphatidylinositol 3-Kinase, BAF250a, PHOSPHATIDYLINOSITOL 3-KINASE, Trans Acting, diseases, DmelCG2699, F8A5.4, MDA-BF-1, diseases and disorders, p110alpha, High-Throughput Biological Assays, mGlu8, Transforming, phosphatidylinositol 3-kinase activity, GLUR8, human disease, Endometrium Carcinomas, Biology, TAF-I, Pi3K92D, CG4141, Endometrium Cancers, Complete Exome Sequencing, Whole Transcriptome Sequencing, catalyst activity, hypoplasia, Pi3k, Oncogeneses, MK2, AA960234, Endometrium Cancer, PI[[3]]K, Bio-Informatic, INSDC_feature:ncRNA, PKB|Akt, IGAAD, p55alpha, DmelCG10574, Endometrium Carcinoma, Bio-Informatics, Wnt11r, erbB3-S, mGlur, gamma-sarcoglycan, Malignancies, Rps6kc1, Pi3K, PI3k, MCMTC, Endometrial Carcinoma, phapii, Interfering RNA, Carcinoma, PI3K68D, Trans-Acting siRNA, dakt, D330034O08, P110DELTA, PtdIns-3-kinase activity, SG-gamma, R75373, StF-IT-1, D630041K24Rik, XLG2, l(3)89Bq, vacuolar protein sorting 34, dPIK, 1-phosphatidylinositol 3-kinase activity, IGgfbp3, PKB/Akt, PKB/AKT, organ of sensory organ system, dAkt, dAKT, Small Scan, Diseases, Genetic Materials, B120, Short Interfering RNA, DAkt, regulator, Hairpin RNA, Scan, Genetic Material, Lines, l(3)04226, DPKB, Bioinformatic, pAkt, p85alpha, High-Throughput Biological Assay, mGluR8b, KIAA0998, CG4299, PI3K 68_D, gamma (35kDa dystrophin-associated glycoprotein), Endometrial Cancers, Endometrium, disease, p110D, DMDA, Dakt, Oncogenesis, Specificity and Sensitivity, dPKB, Xwnt11, sense organ system organ, Cistron, medical condition., p120-PI3K, AA682037, i2pp2a, Transcriptome Sequencings, droPIK57, DRAC-PK85, other disease, Tumorigeneses, SGCG_HUMAN, LGCR, Complete Exome, PI3K92E, AL023020, Benign Neoplasm, Gene, Pi3K_59F, Coding, type I phosphatidylinositol kinase activity, Malignant, STAMP, TYPE, PHAPII, phosphatidylinositol 3-kinase, DAGA4, Dpkb, Short Hairpin RNA, hELD, AI447310, reduced, p60, Scan RNA, 35DAG, PHOSPATIDYLINOSITOL 3-KINASE, tiny, wnt11-r, endometrial cancer, SCG3, sensitivity, Dp110/PI3K, PI3K-68D/E, study, WES, Cancer of the Endometrium, Genetic, Malignancy, Mglur8, Medical Coding, ipp2a2, Gprc1h, PI3'K, 4930556H18Rik, non-neoplastic, A230002O04, Rpk118, PYK, High-Throughput Screening Method, Stamp, PI3K-68D, Cancer Genes, taf-ibeta, DRAC-PK, disorder, Sensitivity, High-Throughput, 1 Phosphatidylinositol 3 Kinase, Carcinoma of Endometrium, Sinnesorgan, small, dP110, Molecular Biology, EDF, 6330412C24Rik, p120, High-Throughput Screenings, igaad, Cell Lines, p110, IGFBP-3, TRPS1, Vps34p, medical condition, Tumorigenesis, Cistrons, Bioinformatics, group, LGMD2C, p180-ErbB3, sensory system organ, malignant neoplasm of endometrium, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, vps34, I2PP2A, Xwnt-11, nuc-ErbB3, dp110, D-Akt, High-Throughput Chemical Assay, PI3CG, BP-53, PI-3-K, tumour of endometrium, C1orf4, PI3K-59F, Genes, Complete Transcriptome Sequencing, c-erbB-3, PI3K-Dp110, akt1, dAkt1, Endometrial Carcinomas, sensory organ system organ, DRAC-PK66, XLG, class III, p110gamma, Neoplasm Gene, Fif, dSET/TAF-Ibeta, 2610030F17Rik, dakt1, MK-2, PKBalpha, SCARMD2, tumor of endometrium, mGluR8, dAKT1, RAC, Rac, AA407739, Her3, HER3falseena-DATASET-MDACC-22-07-2012-17:29:58:085-32 - samplesMDACC-endo2017-07-26 15:39:24EGAD00001000201960623028188EGAC00001000066EGAS00001000318