Dataset Information

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

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.).

SUBMITTER: Cancer Genome Atlas Research Network

PROVIDER: S-EPMC4530011 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Brat Daniel J DJ Verhaak Roel G W RG Aldape Kenneth D KD Yung W K Alfred WK Salama Sofie R SR Cooper Lee A D LA Rheinbay Esther E Miller C Ryan CR Vitucci Mark M Morozova Olena O Robertson A Gordon AG Noushmehr Houtan H Laird Peter W PW Cherniack Andrew D AD Akbani Rehan R Huse Jason T JT Ciriello Giovanni G Poisson Laila M LM Barnholtz-Sloan Jill S JS Berger Mitchel S MS Brennan Cameron C Colen Rivka R RR Colman Howard H Flanders Adam E AE Giannini Caterina C Grifford Mia M Iavarone Antonio A Jain Rajan R Joseph Isaac I Kim Jaegil J Kasaian Katayoon K Mikkelsen Tom T Murray Bradley A BA O'Neill Brian Patrick BP Pachter Lior L Parsons Donald W DW Sougnez Carrie C Sulman Erik P EP Vandenberg Scott R SR Van Meir Erwin G EG von Deimling Andreas A Zhang Hailei H Crain Daniel D Lau Kevin K Mallery David D Morris Scott S Paulauskis Joseph J Penny Robert R Shelton Troy T Sherman Mark M Yena Peggy P Black Aaron A Bowen Jay J Dicostanzo Katie K Gastier-Foster Julie J Leraas Kristen M KM Lichtenberg Tara M TM Pierson Christopher R CR Ramirez Nilsa C NC Taylor Cynthia C Weaver Stephanie S Wise Lisa L Zmuda Erik E Davidsen Tanja T Demchok John A JA Eley Greg G Ferguson Martin L ML Hutter Carolyn M CM Mills Shaw Kenna R KR Ozenberger Bradley A BA Sheth Margi M Sofia Heidi J HJ Tarnuzzer Roy R Wang Zhining Z Yang Liming L Zenklusen Jean Claude JC Ayala Brenda B Baboud Julien J Chudamani Sudha S Jensen Mark A MA Liu Jia J Pihl Todd T Raman Rohini R Wan Yunhu Y Wu Ye Y Ally Adrian A Auman J Todd JT Balasundaram Miruna M Balu Saianand S Baylin Stephen B SB Beroukhim Rameen R Bootwalla Moiz S MS Bowlby Reanne R Bristow Christopher A CA Brooks Denise D Butterfield Yaron Y Carlsen Rebecca R Carter Scott S Chin Lynda L Chu Andy A Chuah Eric E Cibulskis Kristian K Clarke Amanda A Coetzee Simon G SG Dhalla Noreen N Fennell Tim T Fisher Sheila S Gabriel Stacey S Getz Gad G Gibbs Richard R Guin Ranabir R Hadjipanayis Angela A Hayes D Neil DN Hinoue Toshinori T Hoadley Katherine K Holt Robert A RA Hoyle Alan P AP Jefferys Stuart R SR Jones Steven S Jones Corbin D CD Kucherlapati Raju R Lai Phillip H PH Lander Eric E Lee Semin S Lichtenstein Lee L Ma Yussanne Y Maglinte Dennis T DT Mahadeshwar Harshad S HS Marra Marco A MA Mayo Michael M Meng Shaowu S Meyerson Matthew L ML Mieczkowski Piotr A PA Moore Richard A RA Mose Lisle E LE Mungall Andrew J AJ Pantazi Angeliki A Parfenov Michael M Park Peter J PJ Parker Joel S JS Perou Charles M CM Protopopov Alexei A Ren Xiaojia X Roach Jeffrey J Sabedot Thaís S TS Schein Jacqueline J Schumacher Steven E SE Seidman Jonathan G JG Seth Sahil S Shen Hui H Simons Janae V JV Sipahimalani Payal P Soloway Matthew G MG Song Xingzhi X Sun Huandong H Tabak Barbara B Tam Angela A Tan Donghui D Tang Jiabin J Thiessen Nina N Triche Timothy T Van Den Berg David J DJ Veluvolu Umadevi U Waring Scot S Weisenberger Daniel J DJ Wilkerson Matthew D MD Wong Tina T Wu Junyuan J Xi Liu L Xu Andrew W AW Yang Lixing L Zack Travis I TI Zhang Jianhua J Aksoy B Arman BA Arachchi Harindra H Benz Chris C Bernard Brady B Carlin Daniel D Cho Juok J DiCara Daniel D Frazer Scott S Fuller Gregory N GN Gao JianJiong J Gehlenborg Nils N Haussler David D Heiman David I DI Iype Lisa L Jacobsen Anders A Ju Zhenlin Z Katzman Sol S Kim Hoon H Knijnenburg Theo T Kreisberg Richard Bailey RB Lawrence Michael S MS Lee William W Leinonen Kalle K Lin Pei P Ling Shiyun S Liu Wenbin W Liu Yingchun Y Liu Yuexin Y Lu Yiling Y Mills Gordon G Ng Sam S Noble Michael S MS Paull Evan E Rao Arvind A Reynolds Sheila S Saksena Gordon G Sanborn Zack Z Sander Chris C Schultz Nikolaus N Senbabaoglu Yasin Y Shen Ronglai R Shmulevich Ilya I Sinha Rileen R Stuart Josh J Sumer S Onur SO Sun Yichao Y Tasman Natalie N Taylor Barry S BS Voet Doug D Weinhold Nils N Weinstein John N JN Yang Da D Yoshihara Kosuke K Zheng Siyuan S Zhang Wei W Zou Lihua L Abel Ty T Sadeghi Sara S Cohen Mark L ML Eschbacher Jenny J Hattab Eyas M EM Raghunathan Aditya A Schniederjan Matthew J MJ Aziz Dina D Barnett Gene G Barrett Wendi W Bigner Darell D DD Boice Lori L Brewer Cathy C Calatozzolo Chiara C Campos Benito B Carlotti Carlos Gilberto CG Chan Timothy A TA Cuppini Lucia L Curley Erin E Cuzzubbo Stefania S Devine Karen K DiMeco Francesco F Duell Rebecca R Elder J Bradley JB Fehrenbach Ashley A Finocchiaro Gaetano G Friedman William W Fulop Jordonna J Gardner Johanna J Hermes Beth B Herold-Mende Christel C Jungk Christine C Kendler Ady A Lehman Norman L NL Lipp Eric E Liu Ouida O Mandt Randy R McGraw Mary M Mclendon Roger R McPherson Christopher C Neder Luciano L Nguyen Phuong P Noss Ardene A Nunziata Raffaele R Ostrom Quinn T QT Palmer Cheryl C Perin Alessandro A Pollo Bianca B Potapov Alexander A Potapova Olga O Rathmell W Kimryn WK Rotin Daniil D Scarpace Lisa L Schilero Cathy C Senecal Kelly K Shimmel Kristen K Shurkhay Vsevolod V Sifri Suzanne S Singh Rosy R Sloan Andrew E AE Smolenski Kathy K Staugaitis Susan M SM Steele Ruth R Thorne Leigh L Tirapelli Daniela P C DP Unterberg Andreas A Vallurupalli Mahitha M Wang Yun Y Warnick Ronald R Williams Felicia F Wolinsky Yingli Y Bell Sue S Rosenberg Mara M Stewart Chip C Huang Franklin F Grimsby Jonna L JL Radenbaugh Amie J AJ Zhang Jianan J

The New England journal of medicine 20150610 26

<h4>Background</h4>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 co ...[more]

PMID: 26061751

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Project description:BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and methodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01-1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00-1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00-1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01-1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

Project description:Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

Dataset Information

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Background

Methods

Results

Conclusions

Publications

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

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