The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients

Nicole M. Warrington, Tao Sun, Jingqin Luo, Robert C. McKinstry, Patricia C. Parkin, Sara Ganzhorn, Debra Spoljaric, Anne C. Albers, Amanda Merkelson, Douglas R. Stewart, David A. Stevenson, David Viskochil, Todd E. Druley, Jason T. Forys, Karlyne M. Reilly, Michael J. Fisher, Uri Tabori, Jeffrey C. Allen, Joshua D. Schiffman, David H. GutmannJoshua B. Rubin

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Identifying modifiers of glioma risk in patients with type 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 adenylate cyclase 8 (ADCY8) that 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.

Original languageEnglish
Pages (from-to)16-21
Number of pages6
JournalCancer research
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2015

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