Gene expression profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes.
Pilocytic astrocytomas (PAs) are World Health Organization Grade I gliomas; they most often affect children and young adults and occur in patients with neurofibromatosis type 1 (NF1). To identify genes that are differentially expressed in sporadic (S-PA) versus NF1-associated PAs (NF1-PAs) and those that might reflect differences in clinical behavior, we performed gene expression profiling using Affymetrix U133 Plus2.0 GeneChip arrays in 36 S-PAs and 11 NF1-PAs. Thirteen genes were overexpressed, and another 13 genes were underexpressed in NF1-PAs relative to S-PAs. Immunohistochemical studies performed on 103 tumors, representing 2 independently generated tissue microarrays, confirmed the differential expression of CUGBP2 (p = 0.0014), RANBP9 (p = 0.0075), ITGAV1 (p = 0.0001), and INFGR1 (p = 0.024) proteins. One of the underexpressed genes, aldehyde dehydrogenase 1 family member L1 (ALDH1L1), was also reduced in clinically aggressive compared with typical PAs (p = 0.01) and in PAs with increased cellularity and necrosis. Furthermore, in an additional independent set of tumors, weak to absent ALDH1L1 expression was found in 13 (72%) of 18 clinically aggressive PAs, in 8 (89%) of 9 PAs with pilomyxoid features, in 7 (70%) of 10 PAs with anaplastic transformation, and in 16 (76%) of 21 diffusely infiltrating astrocytomas of various grades. In summary, we have identified a molecular signature that distinguishes NF1-PA from S-PA and found that ALDH1L1 underexpression is associated with aggressive histology and/or biologic behavior.
Rodriguez
Fausto J
FJ
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. Rodriguez.fausto@mayo.edu
Giannini
Caterina
C
Asmann
Yan W
YW
Sharma
Mukesh K
MK
Perry
Arie
A
Tibbetts
Kathleen M
KM
Jenkins
Robert B
RB
Scheithauer
Bernd W
BW
Anant
Shrikant
S
Jenkins
Sarah
S
Eberhart
Charles G
CG
Sarkaria
Jann N
JN
Gutmann
David H
DH
D000293:Adolescent; D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001254:Astrocytoma / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000150:complications*; D000587:Oxidoreductases Acting on CH-NH Group Donors; D050697:Retinal Dehydrogenase; D055815:Young Adult; D000099295:Formyltetrahydrofolate Dehydrogenase
D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D050697:Retinal Dehydrogenase; D000099295:Formyltetrahydrofolate Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse