EGAGenomicsIllumina HiSeq 2500, ILLUMINAOtherhttps://ega-archive.org/studies/EGAS00001002604EGAEGA study EGAS00001002604Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers: multi-timepoint exome sequencing of a single patient's diseaseEGArestrictedDER/faint little ball, Elp-B1RB1, Elp, D-Egf, pulmo, Wa5, l(2)09261, TGF-alpha receptor activity, ERBB, C-erb, dEGFR1, DEgfr, Elp-B1, der, familial, Elp-1, mor1, lung parenchyma, Errb1, mENA, EK2-6, Ximpact, impact-a, CG10079, PIG61, torpedo/egfr, epidermal growth factor receptor activity, wa2, DmelCG10079, epidermal growth factor-activated receptor activity, AI552599, c-erbB, EGFr, Egfr, lung, imprinted and ancient gene protein homolog, IMPACT, torpedo/Egfr, EGF receptor activity, epistatic, TOP, Egf-r, epistatic genetic interaction (sensu inequality), DER/top, d-egf-r, neoplasm, neoplasms, imprinted and ancient gene protein, egfr, EGF-R, HD-33, El, top/DER, DER/EGFR, EGFR, EGfr, EgfR, dEgfr, DER flb, top, Torpedo/DER, ERBB1, wa-2, Torpedo/Egfr, flb, top/flb, Degfr, genetic, parenchyma of lung., Egf, EFG-R, pulmonary, Errp, l(2)57EFa, Erbb, DEGFR, l(2)57DEFa, l(2)05351, Der, DER, 9030024J15Rik, D-EGFR, dEGFR, inherited genetic, l(2)57Ea, Lungs, transforming growth factor-alpha receptor activity, DmHD-33, E430016J11Rik, constitutitional genetic, hereditary, RWDD5, DER/torpedo, HER1, NISBD2, DER1RB1, Forms, l(2)k06503, Dm DWnt3/5, Malignant tumor of lung, DWnt-5, Materials, DWnt-4, dP60, Product, Vps34, acetylglucosaminyltransferase-like protein, Elp-B1, der, Elp-1, Errb1, l(2)wg, BcDNA:LD15217, malignant neoplasm of the lung, RBF, Tumor, Diagnosis, End-Of-Life, VPS34, 11621, PIG61, Case Fatality Rates, PI-3 kinase, p110-alpha, Death Rates, Lung Carcinomas, RBR, wnt-4, int-1, cdk, epidermal growth factor-activated receptor activity, Dm-1, responsivity, Dm-2, Dm-3, symptoms, DmelCG1916, CycE1, RETINOBLASTOMA PROTEIN, Excess Mortalities, rbf, Fs(3)Hor, myd, treatment, Cell Division Cycles, Lung Cancer, Fresh Frozen, Dp60, Biopsies, I, like-acetylglucosaminyltransferase, PI3K_59F, plant peltate hair, Mbp-1, PI3-kinase activity, Lung Cancers, NTef2, WNT, Wnt, PI3Kgamma, flb, allergic reaction, MCAP, medicine, DNA fingerprint, PI3K 68D, Br, 9030024J15Rik, Homo sapiens disease, dWnt2, stage, Age-Specific Death Rate, plasma, wnt, Diagnose, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, Tumors, screening, dVps34, Elp, Data Set, DEgfr, rea, familial, Crude Death, p50alpha, retinoblastoma, DNA fingerprinting, CG2699, DmelCG5373, Diagnoses, Fs(3)Sz11, non-small cell lung cancer, torpedo/egfr, Benign, Postmortem, C530050K14, D-wnt-2, mKIAA0609, type-1 PI3K, ATRBR1, malignant tumour of lung, CG4889, Carcinomas, egfr, fg, CG11621, Lung malignant tumors, resistance., HD-33, El, DmelCG7413, death rate, AW538188, DER/EGFR, EGFR, EGfr, EgfR, signs, Benign Neoplasms, DER flb, INSDC_feature:gene, Cdk4/6, Torpedo/Egfr, DmelCG4141, F8A5_4, Malignant Neoplasms, Degfr, APDS, MDC1D, Mortality Rate, enr, antagonists and inhibitors, familial retinoblastoma, Material, DEGFR, PI3KBETA, l(2)05351, CG2684, l(2)0671, Cancer of the Lung, lung neoplasm, Mortality Determinant, DNA finger printing, other neoplasm, Fresh, Lung, D-Egf, Fresh Frozen Plasma, Neoplasms, developmental stage, peltate hair, lung cancer, number, Excess, Crude Mortality Rate, non-small cell carcinoma of the lung, mENA, EK2-6, dRBF, LARGE1, Age-Specific Death, PIK3, Rate, Determinant, Cardiac, cyclinE, dVps34/PI3K59F, Pi3Kp60, sensitive, PI3K-dp110, EGFr, Egfr, disease or disorder, Screening, Case Fatality, torpedo/Egfr, dPI3K, TOP, anon-92Ed, Antemortem, Pulmonary Cancer, Pulmonary, class I, Cycles, Differential Mortality, malignant tumour of the lung, Excess Mortality, DmelCG6407, MDDGB6, Cell Division Cycle, LNCR, cell-division cycle, top, dWnt, Diagnoses and Examinations, Pi3Kp110, Lung Carcinoma, P110BETA, Neoplasias, NSCLC, cdk4, drugs, Wnt3/5, DmelCG4698, PI3K21B, Lung Neoplasm, malignant neoplasm of lung, Crude Death Rates, CDK4, MCM, constitutitional genetic, l(2)05428, Pharmaceuticals, Cancer, Cpk, Elp-B1RB1, inhibitors, Products, Antemortem Diagnoses, findings, Malignant Neoplasm, Mortality Decline, AA414921, l(2)rO727, TGF-alpha receptor activity, class II, ERBB, dEGFR1, type III phosphoinositide 3-kinase activity, disorders, Cell, PI(3)K, cpk, PI3K-92E/Dp110, Frozen Plasmas, Case Fatality Rate, PIK3C1, spd, MT, CWS5, chemical analysis, post-mortem, Neoplasm, malignant lung tumour, Nonsmall cell lung cancer, PPP1R130, condition, Non-small cell lung cancer, DER/top, scales, Death, malignant tumor of the lung, Death Rate, primary cancer, Pharmaceutic Preparations, Pulmonary Neoplasm, CG4698, Cancers, Crk3, DmelCG11621, Understanding, wa-2, Lds, malignant tumor, caPI3K, Differential, CLOVE, like-glycosyltransferase, DmVps34, IMD14, Erbb, PI3K_68D, PI3K-92D, Decline, protection against, Pk53C, Pulmonary Cancers, Dmp110, biopsy, DWnt-3, Pharmaceutical Products, DWnt-2, hereditary, DWnt-1, Neoplasia, Differential Mortalities, Non-Small-Cell, CG6407, DER/faint little ball, deceased, scale tissue, Antemortem Diagnosis, insensitive, CCNE, CG5373, determination, ATVPS34, Dint-1, DmelCG4889, selection process, Blood, Mbp1, Non-Small Cell Lung Cancer, cdk4/6, malignant tumor of lung, PI3K, Dp110, Cardiac Death, temporal, Readability, PHOSPHATIDYLINOSITOL 3-KINASE, Ccne, diseases, DmelCG2699, F8A5.4, AI552599, Pharmaceutical Product, Non-Small-Cell Lung Carcinoma, RB, rb, diseases and disorders, p110alpha, cytopathology, phosphatidylinositol 3-kinase activity, Non-Small Cell Lung Carcinoma, Dm Wg, d-egf-r, ccne, Wnt-4, l(2)02657, Wnt-1, Pulmonary cancer, Wnt-3, Wnt-2, Fresh Frozen Plasmas, human disease, DmelCG2684, Crude Mortality Rates, Pi3K92D, CG4141, pp110, alveolar cell carcinoma, cycE3, Rb, catalyst activity, Pi3k, Non-Small Cell Lung, End Of Life, PI[[3]]K, Non Small Cell Lung Carcinoma, DWnt5, free, DWnt4, DWnt3, DWnt2, genetic, resistance to, p55alpha, Malignant neoplasm of lung, malignant neoplasm, Dwnt5, Pharmaceutical, CFR Case Fatality Rate, Cell Cycles, Dwnt4, disease management, dCdk4, Therapies, D-EGFR, Malignancies, CG7413, Pi3K, PI3k, associated, MCMTC, somatic mutation, NISBD2, DNA profiling, Sp, DER1, Therapy, Carcinoma, retinoblastoma-related 1, PI3K68D, Lung cancer, Frozen Plasma, Wa5, l(2)09261, gyltl1b-b, P110DELTA, PtdIns-3-kinase activity, rbf1, incomplete, Cancer of Lung, somatic, Plasmas, RETINOBLASTOMA 1, results, CG10079, hereditary retinoblastoma, vacuolar protein sorting 34, Division Cycles, Crude Mortality, dPIK, 1-phosphatidylinositol 3-kinase activity, abolished, Mortality, Screenings, clone 2.4, wa2, cancer of lung, MDDGA6, Examinations and Diagnoses, Diseases, Genetic Materials, Malignant lung tumor, Near-Death Experience, Pharmaceutic, epistatic genetic interaction (sensu inequality), Postmortem Diagnosis, DWint-1, KIAA0609, non-small cell lung carcinoma (disease), Genetic Material, acetylglucosaminyltransferase-like 1A, DWnt3/5, Diagnoses and Examination, pRb, Postmortem Diagnoses, malignant lung neoplasm, gyltl1b, histopathology, Drives, resistant, Division Cycle, anon-WO03040301.228, p85alpha, Determination of Death, adenocarcinoma of lung, anon-EST:Liang-2.4, susceptibility to, dEgfr, WG, mdc1d, Mortalities, PI3K 68_D, LARGE_HUMAN, Treatments, Non Small Cell Lung, early, response to tyrosine kinase inhibitor in, non-small cell carcinoma of lung, disease, p105-Rb, metastatic, CDK4/6, CG1916, p110D, Crude Death Rate, Patient, Horka, l(2)57DEFa, Wg, Fs(3)Horka, dEGFR, Cistron, inherited genetic, DmHD-33, p120-PI3K, EG:34F3.3, droPIK57, Rbf1, RBF1, Cancer of the lung, other disease, xcdk4, FBF, non-small cell lung carcinoma, Mortality Declines, C-erb, malignant lung tumor, PI3K92E, Benign Neoplasm, mor1, Gene, Pi3K_59F, Pk?7, Non-Small-Cell Lung, type I phosphatidylinositol kinase activity, Malignant, mortality measurement, autosomal dominant, presence, DWnt-3/5, froggy, CYCLE, phosphatidylinositol 3-kinase, Gyltl1a, Mortality Determinants, Crude, non-small cell cancer of the lung, eye cancer, p60, c-erbB, Cycle, Mass, OSRC, EGF receptor activity, PHOSPATIDYLINOSITOL 3-KINASE, NSCLC - non-small cell lung cancer, Egf-r, DmF2, sensitivity, Dp110/PI3K, PI3K-68D/E, Drugs, lod, reactivity, study, Blood Plasma, EGF-R, Genetic, Malignancy, CG5072, inhibiteur, Torpedo/DER, Cell Division, PSK-J3, LARGE, PI3'K, Age-Specific, Wnt/Wg, Wnt1, top/flb, Wnt3, non-neoplastic, wnt4, wnt3, wnt2, BPFD#36, wnt1, PI3K-68D, inhibidor, l(2)57EFa, Clients, Blood Plasmas, Mortality Rates, mortality rate, Nonsmall Cell Lung Cancer, CMM3, wnt5, disorder, l(2)57Ea, Preparation, Age Specific Death Rate, Non-Small-Cell Lung Carcinomas, incidence, dP110, Pulmonary Neoplasms, 6330412C24Rik, p120, drug, p110, inhibitor, Vps34p, medical condition, Cistrons, Client, Examination and Diagnoses, wgl, l(2)s4639, count in organism, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, survival, epidermal growth factor receptor activity, DmelCG10079, vps34, Mass Screenings, dp110, epistatic, PI3CG, Determinants, DmCdk4, antagonists, PI-3-K, Plasma, Rates, death, PI3K-59F, distinct, scale, top/DER, PI3K-Dp110, Rb-1, class III, portion of plasma, Dwnt-2, Dwnt-3, ERBB1, patient, Age-Specific Death Rates, DmelCG5072, p110gamma, Dm DWnt2, Dm DWnt4, Drug, Rb1, 8-6, Preparations, Egf, nonsmall cell lung cancer, EFG-R, Therapeutic, Errp, Dwnt-5, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Der, DER, Treatment, transforming growth factor-alpha receptor activity, assay, response, non-small cell cancer of lung, RbF, trilateral, DER/torpedo, l(2)sh0671, HER1, Gla, Pharmaceutical Preparation, glycosyltransferase-like protein LARGE1falseEvolution and clinical impact of genetic epistasis within EGFR-mutant lung cancersThe current understanding of tumorigenesis is largely centered on a monogenic driver oncogene model. This paradigm is incompatible with the prevailing clinical experience in most solid malignancies: monotherapy with a drug directed against an individual oncogenic driver typically results in incomplete clinical responses and eventual tumor progression1-7. By profiling the somatic genetic alterations present in over 2,000 cases of lung cancer, the leading cause of cancer mortality worldwide, we show that combinations of functional genetic alterations, i.e. genetic collectives dominate the landscape of advanced-stage disease. We highlight this polygenic landscape and evolution of advanced-stage non-small cell lung cancer (NSCLC) through the spatial-temporal genomic profiling of 7 distinct tumor biopsy specimens and 6 plasma specimens obtained from an EGFR-mutant NSCLC patient at (1) initial diagnosis of early-stage disease, (2) metastatic progression, (3) sequential treatment and resistance to 2 EGFR inhibitors, (4) death. The comprehensive genomic analysis of this case, coupled with circulating free (cf) tumor DNA profiling of additional advanced-stage EGFR-mutant NSCLC clinical cohorts with associated treatment responses uncovered features of evolutionary selection for multiple concurrent gene alterations: including the presence of EGFR inhibitor-sensitive (EGFRL858R;EGFRexon19del) or inhibitor-resistant (EGFRT790M;EGFRC797S) forms of oncogenic EGFR along with cell cycle gene alterations (e.g. in CDK4/6, CCNE1, RB1) and activating alterations in WNT/β-catenin and PI3K pathway genes, which our data suggest can cooperatively impart non-redundant functions to limit EGFR targeted therapy response and/or promote tumor progression. Moreover, evidence of an unanticipated parallel evolution of both EGFR T790M and two distinct forms of oncogenic PIK3CA was observed. Our study provides a large-scale clinical and genetic dataset of advanced-stage EGFR-mutant NSCLC, a rationale for specific polytherapy strategies such as EGFR and CDK4/6 inhibitor co-treatment to potentially enhance clinical outcomes, and prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification for targeted therapy. Instead, our findings highlight an alternative model of genetic collectives that operate through epistasis to drive lung cancer progression and therapy resistance.2020-07-16 15:33:08EGAS000010026049606EGAD00001003769EGAC00001000711