Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study

被引:12
作者
Donson, Andrew M. [1 ,2 ,14 ]
Bertrand, Kelsey C. [3 ]
Riemondy, Kent A. [4 ]
Gao, Dexiang [1 ,5 ]
Zhuang, Yonghua [1 ,5 ]
Sanford, Bridget [1 ]
Norris, Gregory A. [1 ,2 ]
Chapman, Rebecca J. [9 ]
Fu, Rui [6 ]
Willard, Nicholas [7 ]
Griesinger, Andrea M. [1 ,2 ]
de Sousa, Graziella Ribeiro [1 ,2 ]
Amani, Vladimir [1 ,2 ]
Grimaldo, Enrique [1 ,2 ]
Hankinson, Todd C. [2 ,8 ]
Booker, Ffyona [9 ]
Sill, Martin [10 ,11 ,12 ]
Grundy, Richard G. [9 ]
Pajtler, Kristian W. [10 ,11 ,12 ,13 ]
Ellison, David W. [3 ]
Foreman, Nicholas K. [1 ,2 ]
Ritzmann, Timothy A. [9 ]
机构
[1] Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO USA
[2] Childrens Hosp Colorado, Morgan Adams Fdn Pediat Brain Tumor Res Program, Aurora, CO USA
[3] St Jude Childrens Res Hosp, Memphis, TN USA
[4] Univ Colorado, RNA Biosci Initiat, Anschutz Med Campus, Aurora, CO USA
[5] Univ Colorado, Canc Ctr Biostat & Bioinformat, Anschutz Med Campus, Aurora, CO USA
[6] New York Genome Ctr, Computat Biol, New York, NY USA
[7] Univ Colorado Denver, Dept Pathol, Aurora, CO USA
[8] Univ Colorado Denver, Dept Neurosurg, Aurora, CO USA
[9] Univ Nottingham, Childrens Brain Tumor Res Ctr, Nottingham, England
[10] Heidelberg KiTZ, Hopp Childrens Canc Ctr, Heidelberg, Germany
[11] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany
[12] German Canc Consortium DKTK, Heidelberg, Germany
[13] Heidelberg Univ Hosp, Dept Pediat Oncol Hematol & Immunol & Pulmonol, Heidelberg, Germany
[14] Univ Colorado, Dept Pediat, 12800 19th Ave,Anschutz Med Campus, Aurora, CO 80045 USA
关键词
chromosomal instability; ependymoma; prognosis; recurrence; SINGLE-CELL; TUMORS; REVEALS; DNA;
D O I
10.1093/neuonc/noad096
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN molecular groups. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA remains largely unknown; however, the increasing use of surgery at first recurrence has now provided access to clinical samples to facilitate a better understanding of this. Methods In this large longitudinal international multicenter study, we examined matched samples of primary and recurrent disease from PFA patients to investigate the biology of recurrence. Results DNA methylome derived copy number variants (CNVs) revealed large-scale chromosome gains and losses at recurrence in PFA. CNV changes were dominated by chromosome 1q gain and/or 6q loss, both previously identified as high-risk factors in PFA, which were present in 23% at presentation but increased to 61% at first recurrence. Multivariate survival analyses of this cohort showed that cases with 1q gain or 6q loss at first recurrence were significantly more likely to recur again. Predisposition to 1q+/6q- CNV changes at recurrence correlated with hypomethylation of heterochromatin-associated DNA at presentation. Cellular and molecular analyses revealed that 1q+/6q- PFA had significantly higher proportions of proliferative neuroepithelial undifferentiated progenitors and decreased differentiated neoplastic subpopulations. Conclusions This study provides clinically and preclinically actionable insights into the biology of PFA recurrence. The hypomethylation predisposition signature in PFA is a potential risk-classifier for trial stratification. We show that the cellular heterogeneity of PFAs evolves largely because of genetic evolution of neoplastic cells.
引用
收藏
页码:1854 / 1867
页数:14
相关论文
共 36 条
[1]   Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study [J].
Adolph, Jonas E. ;
Fleischhack, Gudrun ;
Mikasch, Ruth ;
Zeller, Julia ;
Warmuth-Metz, Monika ;
Bison, Brigitte ;
Mynarek, Martin ;
Rutkowski, Stefan ;
Schueller, Ulrich ;
von Hoff, Katja ;
Obrecht, Denise ;
Pietsch, Torsten ;
Pfister, Stefan M. ;
Pajtler, Kristian W. ;
Witt, Olaf ;
Witt, Hendrik ;
Kortmann, Rolf-Dieter ;
Timmermann, Beate ;
Krauss, Juergen ;
Fruehwald, Michael C. ;
Faldum, Andreas ;
Kwiecien, Robert ;
Bode, Udo ;
Tippelt, Stephan .
NEURO-ONCOLOGY, 2021, 23 (06) :1012-1023
[2]   Characterization of 2 Novel Ependymoma Cell Lines With Chromosome 1q Gain Derived From Posterior Fossa Tumors of Childhood [J].
Amani, Vladimir ;
Donson, Andrew M. ;
Lummus, Seth C. ;
Prince, Eric W. ;
Griesinger, Andrea M. ;
Witt, Davis A. ;
Hankinson, Todd C. ;
Handler, Michael H. ;
Dorris, Kathleen ;
Vibhakar, Rajeev ;
Foreman, Nicholas K. ;
Hoffman, Lindsey M. .
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2017, 76 (07) :595-604
[3]   Pro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma [J].
Aubin, Rachael G. ;
Troisi, Emma C. ;
Montelongo, Javier ;
Alghalith, Adam N. ;
Nasrallah, Maclean P. ;
Santi, Mariarita ;
Camara, Pablo G. .
NATURE COMMUNICATIONS, 2022, 13 (01)
[4]   Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].
Barbie, David A. ;
Tamayo, Pablo ;
Boehm, Jesse S. ;
Kim, So Young ;
Moody, Susan E. ;
Dunn, Ian F. ;
Schinzel, Anna C. ;
Sandy, Peter ;
Meylan, Etienne ;
Scholl, Claudia ;
Froehling, Stefan ;
Chan, Edmond M. ;
Sos, Martin L. ;
Michel, Kathrin ;
Mermel, Craig ;
Silver, Serena J. ;
Weir, Barbara A. ;
Reiling, Jan H. ;
Sheng, Qing ;
Gupta, Piyush B. ;
Wadlow, Raymond C. ;
Le, Hanh ;
Hoersch, Sebastian ;
Wittner, Ben S. ;
Ramaswamy, Sridhar ;
Livingston, David M. ;
Sabatini, David M. ;
Meyerson, Matthew ;
Thomas, Roman K. ;
Lander, Eric S. ;
Mesirov, Jill P. ;
Root, David E. ;
Gilliland, D. Gary ;
Jacks, Tyler ;
Hahn, William C. .
NATURE, 2009, 462 (7269) :108-U122
[5]   Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q [J].
Baroni, Lorena, V ;
Sundaresan, Lakshmikirupa ;
Heled, Ayala ;
Coltin, Hallie ;
Pajtler, Kristian W. ;
Lin, Tong ;
Merchant, Thomas E. ;
McLendon, Roger ;
Faria, Claudia ;
Buntine, Molly ;
White, Christine L. ;
Pfister, Stefan M. ;
Gilbert, Mark R. ;
Armstrong, Terri S. ;
Bouffet, Eric ;
Kumar, Sachin ;
Taylor, Michael D. ;
Aldape, Kenneth D. ;
Ellison, David W. ;
Gottardo, Nicholas G. ;
Kool, Marcel ;
Korshunov, Andrey ;
Hansford, Jordan R. ;
Ramaswamy, Vijay .
NEURO-ONCOLOGY, 2021, 23 (08) :1360-1370
[6]   Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas [J].
Bayliss, Jill ;
Mukherjee, Piali ;
Lu, Chao ;
Jain, Siddhant U. ;
Chung, Chan ;
Martinez, Daniel ;
Sabari, Benjamin ;
Margol, Ashley S. ;
Panwalkar, Pooja ;
Parolia, Abhijit ;
Pekmezci, Melike ;
McEachin, Richard C. ;
Cieslik, Marcin ;
Tamrazi, Benita ;
Garcia, Benjamin A. ;
La Rocca, Gaspare ;
Santi, Mariarita ;
Lewis, Peter W. ;
Hawkins, Cynthia ;
Melnick, Ari ;
Allis, C. David ;
Thompson, Craig B. ;
Chinnaiyan, Arul M. ;
Judkins, Alexander R. ;
Venneti, Sriram .
SCIENCE TRANSLATIONAL MEDICINE, 2016, 8 (366)
[7]   OPTIMISING BIOMARKERS FOR ACCURATE EPENDYMOMA DIAGNOSIS, PROGNOSTICATION AND STRATIFICATION WITHIN INTERNATIONAL CLINICAL TRIALS: A BIOMECA STUDY [J].
Chapman, Rebecca J. ;
Ghasemi, David R. ;
Andreiuolo, Felipe ;
Zschernack, Valentina ;
Espariat, Arnault Tauziede ;
Buttarelli, Francesca ;
Giangaspero, Felice ;
Grill, Jacques ;
Haberler, Christine ;
Paine, Simon M. L. ;
Scott, Ian ;
Jacques, Thomas S. ;
Sill, Martin ;
Stephan, Pfister ;
Kilday, John Paul ;
LeBlond, Pierre ;
Massimino, Maura ;
Modena, Piergiorgio ;
Varlet, Pascale ;
Pietsch, Torsten ;
Grundy, Richard G. ;
Pajtler, Kristian W. ;
Ritzmann, Timothy A. .
NEURO-ONCOLOGY, 2023, 25
[8]  
Childhood Ependymoma Treatment (PDQ(R)): Health Professional Version, 2002, PDQ CANC INF SUMM
[9]   Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma [J].
Donson, Andrew M. ;
Amani, Vladimir ;
Warner, Elliot A. ;
Griesinger, Andrea M. ;
Witt, Davis A. ;
Levy, Jean M. Mulcahy ;
Hoffman, Lindsey M. ;
Hankinson, Todd C. ;
Handler, Michael H. ;
Vibhakar, Rajeev ;
Dorris, Kathleen ;
Foreman, Nicholas K. .
MOLECULAR CANCER THERAPEUTICS, 2018, 17 (09) :1984-1994
[10]   Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups [J].
Dyer, S ;
Prebble, E ;
Davison, V ;
Davies, P ;
Ramani, P ;
Ellison, D ;
Grundy, R .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (06) :2133-2141