The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients

Abstract

Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.

The NF1 gene in tumor syndromes and melanoma

“…An array comparative genomic hybridization (aCGH) study of plexiform neurofibromas from NF1 patients showed a recurrent somatic 9p21.3 deletion involving the antisense noncoding RNA in the INK4 locus (ANRIL) and an association between a germline SNP rs2151280 resulting in reduced ANRIL transcript levels and the number of plexiform neurofibromas, suggesting that ANRIL expression mediated plexiform neurofibromas susceptibility 42 . Polymorphisms in the adenylate cyclase 8 ( ADCY8 ) gene correlated with glioma risk in NF1 patients in a sex-specific manner, elevating the risk in females and reducing it in males, also strengthening the evidence of a role of cAMP in gliomagenesis in NF1 43 . Further studies utilizing genome-wide approaches including genome-wide sequencing appear promising for identification of modifier genes in NF1.…”

“…Animal models expressing mutant Nf1 , including mouse, Drosophila, and zebrafish, show deregulated cAMP levels in various cell types 59–61 . cAMP levels are also altered in human NF1 -associated tumors, including gliomas 43 . There are many other lesser known neurofibromin 1-regulated effectors downstream of RAS, including afadin, adherens junction formation factor (AFDN), ral guanine nucleotide dissociation stimulator (RALGDS), T-cell lymphoma invasion and metastasis 1 (TIAM1), phospholipase C like 1 (PLCL1), and Ras and Rab interactor 1 (RIN1).…”

Survival and causes of death in patients with von Hippel-Lindau disease

“…Recently, different sex-specific patterns of mRNA expression profiles and somatic mutations in genes that may modify VHL -associated tumour phenotypes have been identified in sporadic RCC 26. Accordingly, sex-specific patterns of somatic gene inactivation and activity in cell signalling pathways have been found in CNS gliomas 27 28. Sex differences could be important in the future treatment approaches, both surgical and pharmacological, and needs to be further evaluated.…”

Intersections at the crossroads: Neurofibromatosis type 1, cAMP, sex, and glioma risk

“…Recently, single nucleotide polymorphisms (SNPs) in adenylate cyclase 8 (AC8) were shown to modify the risk for optic pathway gliomas (OPG, brain tumors) in individuals with NF1. 2 These findings revealed one of those confluence points as they not only identified the first genetic modifier of glioma risk in NF1, but also provided the first in-human validation for an oncogenic role of 3 0 -5 0 -cyclic adenosine monophosphate (cAMP) in gliomagenesis. Moreover, and most intriguingly, SNPs in AC8 increased the glioma risk in females while decreasing the risk in males, thus relating the findings to sexual dimorphism in growth regulation by cAMP.…”