Cytogenetic Prognostication Within Medulloblastoma Subgroups

被引：222

作者：

Shih, David J. H. ^{[1
,2
]}

Northcott, Paul A. ^{[6
]}

Remke, Marc ^{[1
,2
]}

Korshunov, Andrey ^{[6
]}

Ramaswamy, Vijay ^{[1
,2
]}

Kool, Marcel ^{[6
]}

Luu, Betty ^{[1
]}

Yao, Yuan ^{[1
,2
]}

Wang, Xin ^{[1
,2
]}

Dubuc, Adrian M. ^{[1
,2
]}

Garzia, Livia ^{[1
]}

Peacock, John ^{[1
,2
]}

Mack, Stephen C. ^{[1
,2
]}

Wu, Xiaochong ^{[1
]}

Rolider, Adi ^{[1
]}

Morrissy, A. Sorana ^{[1
]}

Cavalli, Florence M. G. ^{[1
]}

Jones, David T. W. ^{[6
]}

Zitterbart, Karel ^{[10
,11
]}

Faria, Claudia C. ^{[1
,48
]}

Schueller, Ulrich ^{[8
]}

Kren, Leos ^{[11
]}

Kumabe, Toshihiro ^{[12
]}

Tominaga, Teiji ^{[12
]}

Ra, Young Shin ^{[13
]}

Garami, Miklos ^{[16
]}

Hauser, Peter ^{[16
]}

Chan, Jennifer A. ^{[4
]}

Robinson, Shenandoah ^{[18
]}

Bognar, Laszlo ^{[17
]}

Klekner, Almos ^{[17
]}

Saad, Ali G. ^{[20
]}

Liau, Linda M. ^{[21
]}

Albrecht, Steffen ^{[5
]}

Fontebasso, Adam ^{[5
]}

Cinalli, Giuseppe ^{[25
]}

De Antonellis, Pasqualino ^{[26
]}

Zollo, Massimo ^{[26
,27
]}

Cooper, Michael K. ^{[29
]}

Thompson, Reid C. ^{[29
]}

Bailey, Simon ^{[31
]}

Lindsey, Janet C. ^{[31
]}

Di Rocco, Concezio ^{[28
]}

Massimi, Luca ^{[28
]}

Michiels, Erna M. C. ^{[32
]}

Scherer, Stephen W. ^{[1
]}

Phillips, Joanna J. ^{[22
]}

Gupta, Nalin ^{[22
]}

Fan, Xing ^{[33
]}

Muraszko, Karin M. ^{[33
]}

机构：

[1] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[2] Univ Toronto, Toronto, ON, Canada

[3] McMaster Univ, Hamilton, ON, Canada

[4] Univ Calgary, Calgary, AB, Canada

[5] McGill Univ, Montreal, PQ, Canada

[6] German Canc Res Ctr, Heidelberg, Germany

[7] Univ Heidelberg Hosp, Heidelberg, Germany

[8] Univ Munich, Munich, Germany

[9] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany

[10] Masaryk Univ, Sch Med, Brno, Czech Republic

[11] Univ Hosp Brno, Brno, Czech Republic

[12] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan

[13] Univ Ulsan, Asan Med Ctr, Ulsan, South Korea

[14] Seoul Natl Univ, Childrens Hosp, Seoul, South Korea

[15] Chonnam Natl Univ, Res Inst Med Sci, Hwasun Hosp & Med Sch, Chungnam, South Korea

[16] Semmelweis Univ, H-1085 Budapest, Hungary

[17] Univ Debrecen, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary

[18] Childrens Hosp, Boston, MA 02115 USA

[19] Harvard Univ, Sch Med, Boston, MA USA

[20] Univ Arkansas Med Sci, Little Rock, AR 72205 USA

[21] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[22] Univ Calif San Francisco, San Francisco, CA 94143 USA

[23] Sanford Burnham Med Res Inst, La Jolla, CA USA

[24] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[25] Osped Santobono Pausilipon, Naples, Italy

[26] Univ Naples Federico II, Naples, Italy

[27] Ceinge Biotecnol Avanzate, Naples, Italy

[28] Univ Cattolica Sacro Cuore, Sch Med, I-00168 Rome, Italy

[29] Vanderbilt Univ Sch Med, Nashville, TN USA

[30] St Jude Childrens Res Hosp, Memphis, TN 38105 USA

[31] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[32] Erasmus MC, Rotterdam, Netherlands

[33] Univ Michigan, Sch Med, Ann Arbor, MI USA

[34] Univ Colorado Denver, Aurora, CO USA

[35] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

[36] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA

[37] Univ Lyon, Lyon, France

[38] Inst Curie, Paris, France

[39] INSERM, U830, Paris, France

[40] Univ Paris 05, Paris, France

[41] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA

[42] Washington Univ, St Louis Childrens Hosp, Sch Med, St Louis, MO 63110 USA

[43] Hosp St Joan de Deu, Barcelona, Spain

[44] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[45] Childrens Natl Med Ctr, Washington, DC 20010 USA

[46] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA

[47] Childrens Mem Hlth Inst, Warsaw, Poland

[48] Hosp Santa Maria, Lisbon, Portugal

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2014年 / 32卷 / 09期

关键词：

NEUROTROPHIN RECEPTOR TRKC; CHILDHOOD MEDULLOBLASTOMA; BRAIN-TUMORS; MOLECULAR SUBGROUPS; RISK STRATIFICATION; PATHWAY ACTIVATION; OUTCOME PREDICTION; MYCN AMPLIFICATION; TP53; MUTATIONS; POOR-PROGNOSIS;

D O I：

10.1200/JCO.2013.50.9539

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

引用

页码：886 / +

页数：17

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