CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas

Romain Appay; Caroline Dehais; Claude Alain Maurage; Agusti Alentorn; Catherine Carpentier; Carole Colin; François Ducray; Fabienne Escande; Ahmed Idbaih; Aurélie Kamoun; Yannick Marie; Karima Mokhtari; Emeline Tabouret; Nesrine Trabelsi; Emmanuelle Uro-Coste; Jean Yves Delattre; Dominique Figarella-Branger; F. Dhermain; C. Desenclos; H. Sevestre; P. Menei; A. Rousseau; T. Cruel; S. Lopez; M. I. Mihai; A. Petit; C. Adam; F. Parker; P. Dam-Hieu; I. Quintin-Roué; S. Eimer; H. Loiseau; L. Bekaert; F. Chapon; D. Ricard; C. Godfraind; T. Khallil; D. Cazals-Hatem; T. Faillot; C. Gaultier; M. C. Tortel; I. Carpiuc; P. Richard; W. Lahiani; H. Aubriot-Lorton; F. Ghiringhelli; C. A. Maurage; C. Ramirez; E. M. Gueye; F. Labrousse; O. Chinot; L. Bauchet; V. Rigau; P. Beauchesne; G. Gauchotte; M. Campone; D. Loussouarn; D. Fontaine; F. Vandenbos-Burel; A. Le Floch; P. Roger; C. Blechet; M. Fesneau; A. Carpentier; J. Y. Delattre; S. Elouadhani-Hamdi; M. Polivka; D. Larrieu-Ciron; S. Milin; P. Colin; M. D. Diebold; D. Chiforeanu; E. Vauleon; O. Langlois; A. Laquerriere; F. Forest; M. J. Motso-Fotso; M. Andraud; G. Runavot; B. Lhermitte; G. Noel; S. Gaillard; C. Villa; N. Desse; C. Rousselot-Denis; I. Zemmoura; E. Cohen-Moyal; E. Uro-Coste

doi:10.1093/neuonc/noz124

CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas

Romain Appay, Caroline Dehais, Claude Alain Maurage, Agusti Alentorn, Catherine Carpentier, Carole Colin, François Ducray, Fabienne Escande, Ahmed Idbaih, Aurélie Kamoun, Yannick Marie, Karima Mokhtari, Emeline Tabouret, Nesrine Trabelsi, Emmanuelle Uro-Coste, Jean Yves Delattre, Dominique Figarella-Branger, F. Dhermain, C. Desenclos, H. SevestreP. Menei, A. Rousseau, T. Cruel, S. Lopez, M. I. Mihai, A. Petit, C. Adam, F. Parker, P. Dam-Hieu, I. Quintin-Roué, S. Eimer, H. Loiseau, L. Bekaert, F. Chapon, D. Ricard, C. Godfraind, T. Khallil, D. Cazals-Hatem, T. Faillot, C. Gaultier, M. C. Tortel, I. Carpiuc, P. Richard, W. Lahiani, H. Aubriot-Lorton, F. Ghiringhelli, C. A. Maurage, C. Ramirez, E. M. Gueye, F. Labrousse, O. Chinot, L. Bauchet, V. Rigau, P. Beauchesne, G. Gauchotte, M. Campone, D. Loussouarn, D. Fontaine, F. Vandenbos-Burel, A. Le Floch, P. Roger, C. Blechet, M. Fesneau, A. Carpentier, J. Y. Delattre, S. Elouadhani-Hamdi, M. Polivka, D. Larrieu-Ciron, S. Milin, P. Colin, M. D. Diebold, D. Chiforeanu, E. Vauleon, O. Langlois, A. Laquerriere, F. Forest, M. J. Motso-Fotso, M. Andraud, G. Runavot, B. Lhermitte, G. Noel, S. Gaillard, C. Villa, N. Desse, C. Rousselot-Denis, I. Zemmoura, E. Cohen-Moyal, E. Uro-Coste

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Résumé

Background. The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods. In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results. CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. Conclusions. Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.

langue originale	Anglais
Pages (de - à)	1519-1528
Nombre de pages	10
journal	Neuro-Oncology
Volume	21
Numéro de publication	12
Les DOIs	https://doi.org/10.1093/neuonc/noz124
état	Publié - 1 déc. 2019

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10.1093/neuonc/noz124

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Appay, R., Dehais, C., Maurage, C. A., Alentorn, A., Carpentier, C., Colin, C., Ducray, F., Escande, F., Idbaih, A., Kamoun, A., Marie, Y., Mokhtari, K., Tabouret, E., Trabelsi, N., Uro-Coste, E., Delattre, J. Y., Figarella-Branger, D., Dhermain, F., Desenclos, C., ... Uro-Coste, E. (2019). CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro-Oncology, 21(12), 1519-1528. https://doi.org/10.1093/neuonc/noz124

@article{0dbaee71c7f042c6b70be5f1fc3aac2e,

title = "CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas",

abstract = "Background. The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods. In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results. CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. Conclusions. Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.",

keywords = "Anaplastic astrocytoma, Anaplastic oligodendroglioma, CDKN2A homozygous deletion, Glioblastoma, IDH-mutant, IDH-mutant, IDH-mutant and 1p/19q codeleted, Microvascular proliferation",

author = "Romain Appay and Caroline Dehais and Maurage, {Claude Alain} and Agusti Alentorn and Catherine Carpentier and Carole Colin and Fran{\c c}ois Ducray and Fabienne Escande and Ahmed Idbaih and Aur{\'e}lie Kamoun and Yannick Marie and Karima Mokhtari and Emeline Tabouret and Nesrine Trabelsi and Emmanuelle Uro-Coste and Delattre, {Jean Yves} and Dominique Figarella-Branger and F. Dhermain and C. Desenclos and H. Sevestre and P. Menei and A. Rousseau and T. Cruel and S. Lopez and Mihai, {M. I.} and A. Petit and C. Adam and F. Parker and P. Dam-Hieu and I. Quintin-Rou{\'e} and S. Eimer and H. Loiseau and L. Bekaert and F. Chapon and D. Ricard and C. Godfraind and T. Khallil and D. Cazals-Hatem and T. Faillot and C. Gaultier and Tortel, {M. C.} and I. Carpiuc and P. Richard and W. Lahiani and H. Aubriot-Lorton and F. Ghiringhelli and Maurage, {C. A.} and C. Ramirez and Gueye, {E. M.} and F. Labrousse and O. Chinot and L. Bauchet and V. Rigau and P. Beauchesne and G. Gauchotte and M. Campone and D. Loussouarn and D. Fontaine and F. Vandenbos-Burel and {Le Floch}, A. and P. Roger and C. Blechet and M. Fesneau and A. Carpentier and Delattre, {J. Y.} and S. Elouadhani-Hamdi and M. Polivka and D. Larrieu-Ciron and S. Milin and P. Colin and Diebold, {M. D.} and D. Chiforeanu and E. Vauleon and O. Langlois and A. Laquerriere and F. Forest and Motso-Fotso, {M. J.} and M. Andraud and G. Runavot and B. Lhermitte and G. Noel and S. Gaillard and C. Villa and N. Desse and C. Rousselot-Denis and I. Zemmoura and E. Cohen-Moyal and E. Uro-Coste",

year = "2019",

month = dec,

day = "1",

doi = "10.1093/neuonc/noz124",

language = "English",

volume = "21",

pages = "1519--1528",

journal = "Neuro-Oncology",

issn = "1522-8517",

number = "12",

}

Appay, R, Dehais, C, Maurage, CA, Alentorn, A, Carpentier, C, Colin, C, Ducray, F, Escande, F, Idbaih, A, Kamoun, A, Marie, Y, Mokhtari, K, Tabouret, E, Trabelsi, N, Uro-Coste, E, Delattre, JY, Figarella-Branger, D, Dhermain, F, Desenclos, C, Sevestre, H, Menei, P, Rousseau, A, Cruel, T, Lopez, S, Mihai, MI, Petit, A, Adam, C, Parker, F, Dam-Hieu, P, Quintin-Roué, I, Eimer, S, Loiseau, H, Bekaert, L, Chapon, F, Ricard, D, Godfraind, C, Khallil, T, Cazals-Hatem, D, Faillot, T, Gaultier, C, Tortel, MC, Carpiuc, I, Richard, P, Lahiani, W, Aubriot-Lorton, H, Ghiringhelli, F, Maurage, CA, Ramirez, C, Gueye, EM, Labrousse, F, Chinot, O, Bauchet, L, Rigau, V, Beauchesne, P, Gauchotte, G, Campone, M, Loussouarn, D, Fontaine, D, Vandenbos-Burel, F, Le Floch, A, Roger, P, Blechet, C, Fesneau, M, Carpentier, A, Delattre, JY, Elouadhani-Hamdi, S, Polivka, M, Larrieu-Ciron, D, Milin, S, Colin, P, Diebold, MD, Chiforeanu, D, Vauleon, E, Langlois, O, Laquerriere, A, Forest, F, Motso-Fotso, MJ, Andraud, M, Runavot, G, Lhermitte, B, Noel, G, Gaillard, S, Villa, C, Desse, N, Rousselot-Denis, C, Zemmoura, I, Cohen-Moyal, E & Uro-Coste, E 2019, 'CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas', Neuro-Oncology, VOL. 21, Numéro 12, p. 1519-1528. https://doi.org/10.1093/neuonc/noz124

TY - JOUR

T1 - CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas

AU - Appay, Romain

AU - Dehais, Caroline

AU - Maurage, Claude Alain

AU - Alentorn, Agusti

AU - Carpentier, Catherine

AU - Colin, Carole

AU - Ducray, François

AU - Escande, Fabienne

AU - Idbaih, Ahmed

AU - Kamoun, Aurélie

AU - Marie, Yannick

AU - Mokhtari, Karima

AU - Tabouret, Emeline

AU - Trabelsi, Nesrine

AU - Uro-Coste, Emmanuelle

AU - Delattre, Jean Yves

AU - Figarella-Branger, Dominique

AU - Dhermain, F.

AU - Desenclos, C.

AU - Sevestre, H.

AU - Menei, P.

AU - Rousseau, A.

AU - Cruel, T.

AU - Lopez, S.

AU - Mihai, M. I.

AU - Petit, A.

AU - Adam, C.

AU - Parker, F.

AU - Dam-Hieu, P.

AU - Quintin-Roué, I.

AU - Eimer, S.

AU - Loiseau, H.

AU - Bekaert, L.

AU - Chapon, F.

AU - Ricard, D.

AU - Godfraind, C.

AU - Khallil, T.

AU - Cazals-Hatem, D.

AU - Faillot, T.

AU - Gaultier, C.

AU - Tortel, M. C.

AU - Carpiuc, I.

AU - Richard, P.

AU - Lahiani, W.

AU - Aubriot-Lorton, H.

AU - Ghiringhelli, F.

AU - Maurage, C. A.

AU - Ramirez, C.

AU - Gueye, E. M.

AU - Labrousse, F.

AU - Chinot, O.

AU - Bauchet, L.

AU - Rigau, V.

AU - Beauchesne, P.

AU - Gauchotte, G.

AU - Campone, M.

AU - Loussouarn, D.

AU - Fontaine, D.

AU - Vandenbos-Burel, F.

AU - Le Floch, A.

AU - Roger, P.

AU - Blechet, C.

AU - Fesneau, M.

AU - Carpentier, A.

AU - Delattre, J. Y.

AU - Elouadhani-Hamdi, S.

AU - Polivka, M.

AU - Larrieu-Ciron, D.

AU - Milin, S.

AU - Colin, P.

AU - Diebold, M. D.

AU - Chiforeanu, D.

AU - Vauleon, E.

AU - Langlois, O.

AU - Laquerriere, A.

AU - Forest, F.

AU - Motso-Fotso, M. J.

AU - Andraud, M.

AU - Runavot, G.

AU - Lhermitte, B.

AU - Noel, G.

AU - Gaillard, S.

AU - Villa, C.

AU - Desse, N.

AU - Rousselot-Denis, C.

AU - Zemmoura, I.

AU - Cohen-Moyal, E.

AU - Uro-Coste, E.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Background. The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods. In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results. CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. Conclusions. Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.

AB - Background. The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods. In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results. CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. Conclusions. Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.

KW - Anaplastic astrocytoma

KW - Anaplastic oligodendroglioma

KW - CDKN2A homozygous deletion

KW - Glioblastoma

KW - IDH-mutant

KW - IDH-mutant and 1p/19q codeleted

KW - Microvascular proliferation

UR - http://www.scopus.com/inward/record.url?scp=85076876592&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noz124

DO - 10.1093/neuonc/noz124

M3 - Article

C2 - 31832685

AN - SCOPUS:85076876592

SN - 1522-8517

VL - 21

SP - 1519

EP - 1528

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 12

ER -