PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma.
Pilocytic astrocytomas (PA) are well-differentiated gliomas having a favorable prognosis when compared with other diffuse or infiltrative astrocytomas. Molecular genetic abnormalities and activation of signaling pathways associated with clinically aggressive PA and histologically anaplastic PA have not been adequately studied. We performed molecular genetic, gene expression, and immunohistochemical studies using three PA subsets, including conventional PA (n = 43), clinically aggressive/recurrent PA (n = 24), and histologically anaplastic PA (n = 25). A clinical diagnosis of NF1 was present in 28% of anaplastic PA. Molecular cytogenetic studies demonstrated heterozygous PTEN/10q and homozygous p16 deletions in 6/19 (32%) and 3/15 (20%) cases of anaplastic PA, respectively, but in neither of the two other groups. BRAF duplication was identified in 33% of sporadic anaplastic PA and 63% of cerebellar examples. BRAF (V600E) mutation was absent in four (of 4) sporadic cases lacking duplication. IDH1(R132H) immunohistochemistry was negative in 16 (of 16) cases. Neither PDGFRA nor EGFR amplifications were present. pERK staining levels were similar among the three PA subsets, but a stepwise increase in cytoplasmic pAKT and to a lesser extent pS6 immunoreactivity was noted by immunohistochemistry in aggressive PA groups. This was particularly true in histologically anaplastic PA when compared with conventional PA (p < 0.001 and p = 0.005, respectively). In addition, PTEN expression at the mRNA level was decreased in histologically anaplastic PA when compared to the other groups (p = 0.05). In summary, activation of the PI3K/AKT in addition to MAPK/ERK signaling pathways may underlie biological aggressiveness in PA. Specifically, it may mediate the increased proliferative activity observed in histologically anaplastic PA.
Department of Anatomic Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street SE, Rochester, MN 55905, USA.
Erika F
EF
Rodriguez
Bernd W
BW
Scheithauer
Caterina
C
Giannini
Amanda
A
Rynearson
Ling
L
Cen
Bridget
B
Hoesley
Heather
H
Gilmer-Flynn
Jann N
JN
Sarkaria
Sarah
S
Jenkins
Jin
J
Long
Fausto J
FJ
Rodriguez
D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016543:Central Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human