TY - JOUR
T1 - Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma
AU - Zomerman, Walderik W.
AU - Plasschaert, Sabine L. A.
AU - Conroy, Siobhan
AU - Scherpen, Frank J.
AU - Meeuwsen-de Boer, Tiny G. J.
AU - Lourens, Harm J.
AU - Guerrero Llobet, Sergi
AU - Smit, Marlinde J.
AU - Slagter-Menkema, Lorian
AU - Seitz, Annika
AU - Gidding, Corrie E. M.
AU - Hulleman, Esther
AU - Wesseling, Pieter
AU - Meijer, Lisethe
AU - van Kempen, Leon C.
AU - van den Berg, Anke
AU - Warmerdam, Daniël O.
AU - Kruyt, Frank A. E.
AU - Foijer, Floris
AU - van Vugt, Marcel A. T. M.
AU - den Dunnen, Wilfred F. A.
AU - Hoving, Eelco W.
AU - Guryev, Victor
AU - de Bont, Eveline S. J. M.
AU - Bruggeman, Sophia W. M.
PY - 2018
Y1 - 2018
N2 - The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer.
AB - The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85044111819&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29562177
U2 - 10.1016/j.celrep.2018.02.089
DO - 10.1016/j.celrep.2018.02.089
M3 - Article
C2 - 29562177
VL - 22
SP - 3206
EP - 3216
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
ER -