Abstract
Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
Highlights
Primary brain tumors are the second most common type of cancer in children and the leading cause of cancer-related mortality and morbidity in young patients [1, 2]
We show that it is triggered in pilocytic astrocytomas (PA) through p16INK4a pathway induction following aberrant mitogen-activated protein kinase (MAPK) activation
oncogene-induced senescence (OIS) may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas,andthe highoverall survival ofaffected patients.Clin CancerRes; 17(14); 4650–60.’2011 AACR
Summary
Primary brain tumors are the second most common type of cancer in children (after leukemia) and the leading cause of cancer-related mortality and morbidity in young patients [1, 2]. Pilocytic astrocytomas (PA) are WHO grade I tumors They are the predominant histologic subtype in LGA and the most prevalent CNS neoplasm in childhood, accounting for 23% of all pediatric brain tumors [2]. They occur sporadically throughout childhood and in 15% to 40% of children affected with neurofibromatosis type 1 PAs are slow growing tumors, which often harbor a cystic component They exhibit distinct features, readily distinguishable from other LGAs, including an improved clinical course and prognosis in children, limited proliferation index, and no TP53 mutations or platelet-derived growth factor (PDGF) A/PDGF receptor a (PDGFRa) amplification [6,7,8,9,10].
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