Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations.
OBJECTIVE
Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities.


METHODS
Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing.


RESULTS
Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas.


CONCLUSIONS
Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.
St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Margaret C
MC
Thompson
Christine
C
Fuller
Twala L
TL
Hogg
James
J
Dalton
David
D
Finkelstein
Ching C
CC
Lau
Murali
M
Chintagumpala
Adekunle
A
Adesina
David M
DM
Ashley
Stewart J
SJ
Kellie
Michael D
MD
Taylor
Tom
T
Curran
Amar
A
Gajjar
Richard J
RJ
Gilbertson
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000191:economics; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018579:Patient Selection; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents