Genetic Aberrations Leading to MAPK Pathway Activation Mediate Oncogene-Induced Senescence in Sporadic Pilocytic Astrocytomas

Abstract

Purpose: 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.Experimental Design: 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.Results: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic b-galactosidase activity, low KI-67 index, and induction of p16INK4a 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. Conclusions: 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.

BRAF mutations in pediatric metanephric tumors

“…BRAF V600E mutations occur in tumors that differ greatly in biologic aggressiveness, including melanoma, papillary thyroid cancer, Langerhans cell histiocytosis, pilocytic astrocytoma, and melanocytic nevi [43][44][45][46][47]. In indolent tumors, the BRAF V600E mutation is thought to induce senescence through a mechanism that involves the tumor suppressor gene p16 (INK4a) [48,49]. Although we did not study p16 in our series, all metanephric adenomas studied by Choueiri et al [27] demonstrated nuclear p16 immunoreactivity.…”

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas

“…In contrast, the loss of expression of the neighbor gene p16 has a prognostic impact on PAs [19] . Recently, it was described that the simultaneous loss of expression of p16 and MTAP determines shorter survival of patients with non-small-cell lung cancer [45] .…”

“…Oncogene-induced senescence restricts the progression of benign tumors, such as melanocytic nevi and PAs, in response to V600E BRAF mutation [19,24] . In PAs, the ectopic expression of the V600E BRAF mutation results in induction of the INK4a/ ARF locus, at 9p21, with subsequent overexpression of p16 , a known senescence marker [19,25] , the loss of expression of which correlates with a shorter overall survival (OS) in sporadic PAs [19] and a more aggressive course in some Nf1-PAs [26] .…”

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

“…Although f-BRAF can transform NIH3T3 cells (Jones et al 2008), previous studies have demonstrated that BRAF does not increase astrocyte proliferation (Jacob et al 2009), induces senescence of astrocytes (Jacob et al 2011) and neural stem cells (NSCs) in vitro (Raabe et al 2011), and does not result in gliomagenesis when ectopically expressed in mouse brains in vivo (Robinson et al 2010).…”