Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

被引：296

作者：

Ramaswamy, Vijay ^{[1
,3
,4
]}

Remke, Marc ^{[1
,3
,4
]}

Et, Eric Bouff ^{[2
,3
]}

Faria, Claudia C. ^{[1
,3
,5
]}

Perreault, Sebastien ^{[7
]}

Cho, Yoon-Jae ^{[7
]}

Shih, David J. ^{[1
,3
,4
]}

Luu, Betty ^{[3
]}

Dubuc, Adrian M. ^{[1
,3
,4
]}

Northcott, Paul A. ^{[8
]}

Schueller, Ulrich ^{[10
]}

Gururangan, Sridharan ^{[11
]}

McLendon, Roger ^{[11
]}

Bigner, Darell ^{[11
]}

Fouladi, Maryam ^{[12
]}

Ligon, Keith L. ^{[13
,15
,16
]}

Pomeroy, Scott L. ^{[14
,17
]}

Dunn, Sandra ^{[18
]}

Triscott, Joanna ^{[18
]}

Jabado, Nada ^{[19
]}

Fontebasso, Adam ^{[19
]}

Jones, David T. W. ^{[8
]}

Kool, Marcel ^{[8
]}

Karajannis, Matthias A. ^{[20
]}

Gardner, Sharon L. ^{[20
]}

Zagzag, David ^{[21
,22
]}

Nunes, Sofi A. ^{[23
]}

Pimentel, Jose ^{[6
]}

Mora, Jaume ^{[24
]}

Lipp, Eric ^{[11
]}

Walter, Andrew W. ^{[25
]}

Ryzhova, Marina ^{[26
]}

Zheludkova, Olga ^{[27
]}

Kumirova, Ella ^{[27
]}

Alshami, Jad ^{[19
]}

Croul, Sidney E. ^{[3
]}

Rutka, James T. ^{[1
,3
,4
]}

Hawkins, Cynthia ^{[1
,3
]}

Tabori, Uri ^{[2
,3
]}

Codispoti, Kari-Elise T. ^{[28
]}

Packer, Roger J. ^{[28
]}

Pfister, Stefan M. ^{[8
,29
]}

Korshunov, Andrey ^{[9
,30
]}

Taylor, Michael D. ^{[1
,3
,4
]}

机构：

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

[2] Hosp Sick Children, Div Pediat Hematol Oncol, Toronto, ON M5G 1X8, Canada

[3] Hosp Sick Children, Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada

[4] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[5] Ctr Hosp Lisboa Norte, EPE, Hosp Santa Maria, Div Neurosurg, Lisbon, Portugal

[6] Ctr Hosp Lisboa Norte, EPE, Hosp Santa Maria, Neuropathol Lab, Lisbon, Portugal

[7] Stanford Univ, Dept Neurol, Palo Alto, CA 94304 USA

[8] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[9] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[10] Univ Munich, Ctr Neuropathol, Munich, Germany

[11] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC USA

[12] Cincinnati Childrens Hosp, Div Hematol Oncol, Cincinnati, OH USA

[13] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA

[14] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA

[15] Boston Childrens Hosp, Boston, MA USA

[16] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[17] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA

[18] British Columbia Childrens Hosp, Div Hematol Oncol, Vancouver, BC V6H 3V4, Canada

[19] Montreal Childrens Hosp, Div Pediat Hematol Oncol, Montreal, PQ H3H 1P3, Canada

[20] NYU Langone Med Ctr, Div Pediat Hematol Oncol, New York, NY USA

[21] NYU Langone Med Ctr, Dept Pathol, New York, NY USA

[22] NYU Langone Med Ctr, Dept Neurosurg, New York, NY USA

[23] Inst Portugues Oncol Francisco Gentil, Unidade Neurooncol Pediat, Lisbon, Portugal

[24] Hosp St Joan de Deu Barcelona, Dept Oncol, Barcelona, Spain

[25] Alfred I DuPont Hosp Children, Wilmington, DE USA

[26] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow, Russia

[27] Dmitry Rogachev Fed Res Ctr Pediat Hematol Oncol, Dept Pediat Neurooncol, Moscow, Russia

[28] Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Washington, DC 20010 USA

[29] Univ Heidelberg Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany

[30] Heidelberg Univ, Dept Neuropathol, Heidelberg, Germany

来源：

LANCET ONCOLOGY | 2013年 / 14卷 / 12期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

INTRATUMOR HETEROGENEITY; CHEMOTHERAPY; CHILDREN; DISTINCT; CANCER; ADOLESCENTS; ABERRATIONS; PROGRESSION; PROGNOSIS; EVOLUTION;

D O I：

10.1016/S1470-2045(13)70449-2

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2:samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3:samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0.0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0.0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0.013) than with other subgroups, which was confirmed in cohort 2 (p=0.0075), but not cohort 3 (p=0.70). Interpretation Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

引用

页码：1200 / 1207

页数：8

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