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Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.

Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM - Acta Neuropathol. (2012)

Bottom Line: The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4.For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry.Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.kool@dkfz.de

ABSTRACT
Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

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Related in: MedlinePlus

Overview of chromosomal aberrations in the four medulloblastoma subgroups. Array-CGH and SNP data were scored for loss (green), gain (red), or no change (gray) for all chromosomal arms. Results were plotted as frequencies at which these aberrations occurred within each molecular subgroup. P values on the right indicate whether there was a significant difference in the distribution of these frequencies across the four subgroups (Chi-square test). NS not significant
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Fig2: Overview of chromosomal aberrations in the four medulloblastoma subgroups. Array-CGH and SNP data were scored for loss (green), gain (red), or no change (gray) for all chromosomal arms. Results were plotted as frequencies at which these aberrations occurred within each molecular subgroup. P values on the right indicate whether there was a significant difference in the distribution of these frequencies across the four subgroups (Chi-square test). NS not significant

Mentions: Analysis of the a-CGH and SNP profiling data, available for most cases in five of the seven medulloblastoma series, showed clear differences in chromosomal aberrations as has been reported for each of these series separately [1, 5, 9, 15, 19]. Complete or partial loss of chromosome 6 was found in 35/41 (85%) of WNT-driven tumors, but was nearly absent in all other subgroups (Fig. 2). Loss of 9q was most frequently detected in SHH tumors (47%), but was also found in Group 3 tumors (21%). Loss of 17p with or without concomitant 17q gain was most frequently found in Group 3 (loss 17p: 42%, gain 17q: 62%) and Group 4 (loss 17p: 63%, gain 17q: 73%). Loss of 17p only was also present in the SHH group (25%). Other chromosomal aberrations enriched in specific subgroups included 1q gain (Group 3, 35%), 3q gain (SHH, 27%), 7 gain (Group 3 and 4, 55 and 47%, respectively), 8(p) loss (Group 3 and 4, 33 and 41%, respectively), 8q gain (Group 3, 22%), 10q loss (most frequent in Group 3 (49%) but also present in SHH (26%) and Group 4 (15%)), 12(q) gain in Group 3 (17%) and Group 4 (20%), 16q loss (most frequent in Group 3, 50%), and 18 gain in Group 3 (26%) and Group 4 (16%).Fig. 2


Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.

Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM - Acta Neuropathol. (2012)

Overview of chromosomal aberrations in the four medulloblastoma subgroups. Array-CGH and SNP data were scored for loss (green), gain (red), or no change (gray) for all chromosomal arms. Results were plotted as frequencies at which these aberrations occurred within each molecular subgroup. P values on the right indicate whether there was a significant difference in the distribution of these frequencies across the four subgroups (Chi-square test). NS not significant
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3306778&req=5

Fig2: Overview of chromosomal aberrations in the four medulloblastoma subgroups. Array-CGH and SNP data were scored for loss (green), gain (red), or no change (gray) for all chromosomal arms. Results were plotted as frequencies at which these aberrations occurred within each molecular subgroup. P values on the right indicate whether there was a significant difference in the distribution of these frequencies across the four subgroups (Chi-square test). NS not significant
Mentions: Analysis of the a-CGH and SNP profiling data, available for most cases in five of the seven medulloblastoma series, showed clear differences in chromosomal aberrations as has been reported for each of these series separately [1, 5, 9, 15, 19]. Complete or partial loss of chromosome 6 was found in 35/41 (85%) of WNT-driven tumors, but was nearly absent in all other subgroups (Fig. 2). Loss of 9q was most frequently detected in SHH tumors (47%), but was also found in Group 3 tumors (21%). Loss of 17p with or without concomitant 17q gain was most frequently found in Group 3 (loss 17p: 42%, gain 17q: 62%) and Group 4 (loss 17p: 63%, gain 17q: 73%). Loss of 17p only was also present in the SHH group (25%). Other chromosomal aberrations enriched in specific subgroups included 1q gain (Group 3, 35%), 3q gain (SHH, 27%), 7 gain (Group 3 and 4, 55 and 47%, respectively), 8(p) loss (Group 3 and 4, 33 and 41%, respectively), 8q gain (Group 3, 22%), 10q loss (most frequent in Group 3 (49%) but also present in SHH (26%) and Group 4 (15%)), 12(q) gain in Group 3 (17%) and Group 4 (20%), 16q loss (most frequent in Group 3, 50%), and 18 gain in Group 3 (26%) and Group 4 (16%).Fig. 2

Bottom Line: The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4.For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry.Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.kool@dkfz.de

ABSTRACT
Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

Show MeSH
Related in: MedlinePlus