Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.
| Title: | Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. |
|---|---|
| Authors: | Brat DJ; Verhaak RG; Aldape KD; Yung WK; Salama SR; Cooper LA; Rheinbay E; Miller CR; Vitucci M; Morozova O; Robertson AG; Noushmehr H; Laird PW; Cherniack AD; Akbani R; Huse JT; Ciriello G; Poisson LM; Barnholtz-Sloan JS; Berger MS; Brennan C; Colen RR; Colman H; Flanders AE; Giannini C; Grifford M; Iavarone A; Jain R; Joseph I; Kim J; Kasaian K; Mikkelsen T; Murray BA; O'Neill BP; Pachter L; Parsons DW; Sougnez C; Sulman EP; Vandenberg SR; Van Meir EG; von Deimling A; Zhang H; Crain D; Lau K; Mallery D; Morris S; Paulauskis J; Penny R; Shelton T; Sherman M; Yena P; Black A; Bowen J; Dicostanzo K; Gastier-Foster J; Leraas KM; Lichtenberg TM; Pierson CR; Ramirez NC; Taylor C; Weaver S; Wise L; Zmuda E; Davidsen T; Demchok JA; Eley G; Ferguson ML; Hutter CM; Mills Shaw KR; Ozenberger BA; Sheth M; Sofia HJ; Tarnuzzer R; Wang Z; Yang L; Zenklusen JC; Ayala B; Baboud J; Chudamani S; Jensen MA; Liu J; Pihl T; Raman R; Wan Y; Wu Y; Ally A; Auman JT; Balasundaram M; Balu S; Baylin SB; Beroukhim R; Bootwalla MS; Bowlby R; Bristow CA; Brooks D; Butterfield Y; Carlsen R; Carter S; Chin L; Chu A; Chuah E; Cibulskis K; Clarke A; Coetzee SG; Dhalla N; Fennell T; Fisher S; Gabriel S; Getz G; Gibbs R; Guin R; Hadjipanayis A; Hayes DN; Hinoue T; Hoadley K; Holt RA; Hoyle AP; Jefferys SR; Jones S; Jones CD; Kucherlapati R; Lai PH; Lander E; Lee S; Lichtenstein L; Ma Y; Maglinte DT; Mahadeshwar HS; Marra MA; Mayo M; Meng S; Meyerson ML; Mieczkowski PA; Moore RA; Mose LE; Mungall AJ; Pantazi A; Parfenov M; Park PJ; Parker JS; Perou CM; Protopopov A; Ren X; Roach J; Sabedot TS; Schein J; Schumacher SE; Seidman JG; Seth S; Shen H; Simons JV; Sipahimalani P; Soloway MG; Song X; Sun H; Tabak B; Tam A; Tan D; Tang J; Thiessen N; Triche T Jr; Van Den Berg DJ; Veluvolu U; Waring S; Weisenberger DJ; Wilkerson MD; Wong T; Wu J; Xi L; Xu AW; Yang L; Zack TI; Zhang J; Aksoy BA; Arachchi H; Benz C; Bernard B; Carlin D; Cho J; DiCara D; Frazer S; Fuller GN; Gao J; Gehlenborg N; Haussler D; Heiman DI; Iype L; Jacobsen A; Ju Z; Katzman S; Kim H; Knijnenburg T; Kreisberg RB; Lawrence MS; Lee W; Leinonen K; Lin P; Ling S; Liu W; Liu Y; Liu Y; Lu Y; Mills G; Ng S; Noble MS; Paull E; Rao A; Reynolds S; Saksena G; Sanborn Z; Sander C; Schultz N; Senbabaoglu Y; Shen R; Shmulevich I; Sinha R; Stuart J; Sumer SO; Sun Y; Tasman N; Taylor BS; Voet D; Weinhold N; Weinstein JN; Yang D; Yoshihara K; Zheng S; Zhang W; Zou L; Abel T; Sadeghi S; Cohen ML; Eschbacher J; Hattab EM; Raghunathan A; Schniederjan MJ; Aziz D; Barnett G; Barrett W; Bigner DD; Boice L; Brewer C; Calatozzolo C; Campos B; Carlotti CG Jr; Chan TA; Cuppini L; Curley E; Cuzzubbo S; Devine K; DiMeco F; Duell R; Elder JB; Fehrenbach A; Finocchiaro G; Friedman W; Fulop J; Gardner J; Hermes B; Herold-Mende C; Jungk C; Kendler A; Lehman NL; Lipp E; Liu O; Mandt R; McGraw M; Mclendon R; McPherson C; Neder L; Nguyen P; Noss A; Nunziata R; Ostrom QT; Palmer C; Perin A; Pollo B; Potapov A; Potapova O; Rathmell WK; Rotin D; Scarpace L; Schilero C; Senecal K; Shimmel K; Shurkhay V; Sifri S; Singh R; Sloan AE; Smolenski K; Staugaitis SM; Steele R; Thorne L; Tirapelli DP; Unterberg A; Vallurupalli M; Wang Y; Warnick R; Williams F; Wolinsky Y; Bell S; Rosenberg M; Stewart C; Huang F; Grimsby JL; Radenbaugh AJ; Zhang J |
| Corporate Authors: | Cancer Genome Atlas Research Network |
| Source: | The New England journal of medicine [N Engl J Med] 2015 Jun 25; Vol. 372 (26), pp. 2481-98. Date of Electronic Publication: 2015 Jun 10. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Massachusetts Medical Society Country of Publication: United States NLM ID: 0255562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1533-4406 (Electronic) Linking ISSN: 00284793 NLM ISO Abbreviation: N Engl J Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Boston, Massachusetts Medical Society. |
| MeSH Terms: | Genes, p53* ; Mutation*; DNA, Neoplasm/*analysis ; Glioma/*genetics; Glioblastoma/genetics ; Glioma/metabolism ; Glioma/mortality ; Adolescent ; Adult ; Aged ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 19 ; Cluster Analysis ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasm Grading ; Proportional Hazards Models ; Sequence Analysis, DNA ; Signal Transduction |
| Abstract: | Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.; Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.; Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.; Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.). |
| Comments: | Comment in: N Engl J Med. 2015 Jun 25;372(26):2555-7. doi: 10.1056/NEJMe1506813.. (PMID: 26061754); Comment in: Nat Rev Clin Oncol. 2015 Sep;12(9):502. doi: 10.1038/nrclinonc.2015.111.. (PMID: 26169923) |
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| Grant Information: | U24CA143840 United States CA NCI NIH HHS; U24CA126561 United States CA NCI NIH HHS; P30 CA016672 United States CA NCI NIH HHS; U24 CA143882 United States CA NCI NIH HHS; U54 HG003067 United States HG NHGRI NIH HHS; U54HG003273 United States HG NHGRI NIH HHS; U24 CA143835 United States CA NCI NIH HHS; U24CA143731 United States CA NCI NIH HHS; U24CA126551 United States CA NCI NIH HHS; U24CA126543 United States CA NCI NIH HHS; U24CA126554 United States CA NCI NIH HHS; U24 CA143866 United States CA NCI NIH HHS; U24CA143858 United States CA NCI NIH HHS; U24CA126544 United States CA NCI NIH HHS; P30CA016672 United States CA NCI NIH HHS; U24CA143882 United States CA NCI NIH HHS; U24 CA126551 United States CA NCI NIH HHS; U24CA144025 United States CA NCI NIH HHS; U54HG003067 United States HG NHGRI NIH HHS; U24 CA143845 United States CA NCI NIH HHS; U24 CA143799 United States CA NCI NIH HHS; U01 CA168394 United States CA NCI NIH HHS; U54 HG003273 United States HG NHGRI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; U24 CA144025 United States CA NCI NIH HHS; U24 CA194362 United States CA NCI NIH HHS; U24CA143883 United States CA NCI NIH HHS; U54HG003079 United States HG NHGRI NIH HHS; U24 CA126554 United States CA NCI NIH HHS; U24 CA180951 United States CA NCI NIH HHS; U24 CA143840 United States CA NCI NIH HHS; U24 CA143843 United States CA NCI NIH HHS; U24CA143867 United States CA NCI NIH HHS; U24CA143835 United States CA NCI NIH HHS; U24 CA126561 United States CA NCI NIH HHS; U24 CA143858 United States CA NCI NIH HHS; U24CA143843 United States CA NCI NIH HHS; R01 NS081125 United States NS NINDS NIH HHS; U24 CA143848 United States CA NCI NIH HHS; U24 CA126543 United States CA NCI NIH HHS; U24CA143848 United States CA NCI NIH HHS; U24CA126563 United States CA NCI NIH HHS; U24CA126546 United States CA NCI NIH HHS; U54 HG003079 United States HG NHGRI NIH HHS; U24CA143799 United States CA NCI NIH HHS; U54 HG007990 United States HG NHGRI NIH HHS; U24 CA143883 United States CA NCI NIH HHS; R01 CA163722 United States CA NCI NIH HHS; U24CA143866 United States CA NCI NIH HHS; U24CA143845 United States CA NCI NIH HHS; U24 CA143867 United States CA NCI NIH HHS; U24 CA126546 United States CA NCI NIH HHS; U24 CA126563 United States CA NCI NIH HHS; U24 CA126544 United States CA NCI NIH HHS |
| Contributed Indexing: | Investigator: DJ Brat; RG Verhaak; SR Salama; L Cooper; KD Aldape; WK Yung; R Akbani; JS Barnholtz-Sloan; MS Berger; C Brennan; CA Bristow; AD Cherniack; G Ciriello; R Colen; H Colman; AE Flanders; C Giannini; M Grifford; JT Huse; A Iavarone; R Jain; I Joseph; J Kim; K Kasaian; PW Laird; T Mikkelsen; C Miller; O Morozova; BA Murray; H Noushmehr; BP O'Neill; L Pachter; DW Parsons; LM Poisson; E Rheinbay; A Robertson; C Sougnez; EP Sulman; SR Vandenberg; EG Van Meir; M Vitucci; A von Deimling; K Yoshihara; H Zhang; S Zheng; D Crain; K Lau; D Mallery; S Morris; J Paulauskis; R Penny; T Shelton; M Sherman; P Yena; A Black; J Bowen; K Dicostanzo; J Gastier-Foster; KM Leraas; TM Lichtenberg; CR Pierson; NC Ramirez; C Taylor; S Weaver; L Wise; E Zmuda; T Davidsen; JA Demchok; G Eley; ML Ferguson; CM Hutter; KR Mills Shaw; BA Ozenberger; M Sheth; HJ Sofia; R Tarnuzzer; Z Wang; L Yang; JC Zenklusen; B Ayala; J Baboud; S Chudamani; MA Jensen; J Liu; T Pihl; R Raman; Y Wan; Y Wu; A Ally; JT Auman; M Balasundaram; S Balu; SB Baylin; R Beroukhim; MS Bootwalla; R Bowlby; CA Bristow; D Brooks; Y Butterfield; R Carlsen; S Carter; AD Cherniack; L Chin; A Chu; E Chuah; K Cibulskis; A Clarke; SG Coetzee; N Dhalla; T Fennell; S Fisher; S Gabriel; G Getz; R Gibbs; JL Grimsby; R Guin; A Hadjipanayis; D Hayes; T Hinoue; K Hoadley; RA Holt; AP Hoyle; F Huang; SR Jefferys; S Jones; CD Jones; K Kasaian; R Kucherlapati; PH Lai; PW Laird; E Lander; S Lee; L Lichtenstein; Y Ma; DT Maglinte; HS Mahadeshwar; MA Marra; M Mayo; S Meng; ML Meyerson; PA Mieczkowski; RA Moore; LE Mose; AJ Mungall; BA Murray; H Noushmehr; A Pantazi; M Parfenov; PJ Park; JS Parker; CM Perou; A Protopopov; X Ren; E Rheinbay; J Roach; A Robertson; M Rosenberg; TS Sabedot; S Sadeghi; J Schein; SE Schumacher; JG Seidman; S Seth; H Shen; JV Simons; P Sipahimalani; MG Soloway; X Song; C Sougnez; C Stewart; H Sun; B Tabak; A Tam; D Tan; J Tang; N Thiessen; T Triche; DJ Van Den Berg; U Veluvolu; S Waring; DJ Weisenberger; MD Wilkerson; T Wong; J Wu; L Xi; AW Xu; L Yang; TI Zack; J Zhang; B Aksoy; H Arachchi; C Benz; B Bernard; D Carlin; L Chin; J Cho; D DiCara; S Frazer; GN Fuller; J Gao; N Gehlenborg; G Getz; D Haussler; DI Heiman; L Iype; A Jacobsen; Z Ju; S Katzman; J Kim; H Kim; T Knijnenburg; RB Kreisberg; MS Lawrence; W Lee; K Leinonen; P Lin; S Ling; W Liu; Y Liu; Y Liu; Y Lu; G Mills; S Ng; MS Noble; E Paull; AJ Radenbaugh; A Rao; S Reynolds; G Saksena; Z Sanborn; C Sander; N Schultz; Y Senbabaoglu; R Shen; I Shmulevich; R Sinha; J Stuart; S Sumer; Y Sun; N Tasman; BS Taylor; RG Verhaak; D Voet; N Weinhold; JN Weinstein; D Yang; K Yoshihara; H Zhang; W Zhang; S Zheng; L Zou; T Abel; DJ Brat; ML Cohen; J Eschbacher; C Giannini; EM Hattab; CR Pierson; A Raghunathan; MJ Schniederjan; D Aziz; G Barnett; JS Barnholtz-Sloan; W Barrett; DD Bigner; L Boice; C Brewer; C Calatozzolo; CG Carlotti; TA Chan; L Cuppini; E Curley; S Cuzzubbo; K Devine; F DiMeco; R Duell; JB Elder; A Fehrenbach; G Finocchiaro; W Friedman; J Fulop; J Gardner; B Hermes; A Kendler; NL Lehman; E Lipp; O Liu; R Mandt; M McGraw; R McLendon; C McPherson; L Neder; P Nguyen; A Noss; R Nunziata; BP O'Neill; QT Ostrom; C Palmer; A Perin; B Pollo; A Potapov; O Potapova; W Rathmell; D Rotin; L Scarpace; C Schilero; K Senecal; K Shimmel; V Shurkhay; S Sifri; R Singh; AE Sloan; K Smolenski; SM Staugaitis; R Steele; L Thorne; DP Tirapelli; M Vallurupalli; Y Wang; R Warnick; F Williams; Y Wolinsky; J Zhang; S Bell; B Campos; C Herold-Mende; C Jungk; A Unterberg |
| Substance Nomenclature: | 0 (DNA, Neoplasm) |
| Entry Date(s): | Date Created: 20150611 Date Completed: 20150702 Latest Revision: 20231212 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC4530011 |
| DOI: | 10.1056/NEJMoa1402121 |
| PMID: | 26061751 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural