The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.
Identifying modifiers of glioma risk in patients with type I 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.
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Nicole M
NM
Warrington
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Tao
T
Sun
Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri.
Jingqin
J
Luo
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri.
Robert C
RC
McKinstry
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Patricia C
PC
Parkin
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Sara
S
Ganzhorn
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Debra
D
Spoljaric
Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
Anne C
AC
Albers
Department of Pediatrics, New York University Langone Medical Center, New York, New York.
Amanda
A
Merkelson
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland.
Douglas R
DR
Stewart
Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
David A
DA
Stevenson
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
David
D
Viskochil
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Todd E
TE
Druley
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Jason T
JT
Forys
Rare Tumors Initiative, Office of the Director, Center for Cancer Research, National Cancer Institute, NCI, Bethesda, Maryland.
Karlyne M
KM
Reilly
Division of Oncology, The Children's Hospital of Philadelphia, Pennsylvania. Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Michael J
MJ
Fisher
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Uri
U
Tabori
Department of Pediatrics, New York University Langone Medical Center, New York, New York.
Jeffrey C
JC
Allen
Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
Joshua D
JD
Schiffman
Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
David H
DH
Gutmann
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri. Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri. rubin_j@kids.wustl.edu.
Joshua B
JB
Rubin
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D012737:Sex Factors; D015398:Signal Transduction
D000242:Cyclic AMP