title: Cyclic AMP and c-KIT signaling in familial testicular germ cell tumor predisposition.
abstract: BACKGROUND
  Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined interaction of multiple low-penetrance genes. We reported inactivating germline mutations of the cAMP-binding phosphodiesterase 11A (PDE11A) as modifiers of FTGCT risk. Recent genome-wide association studies have identified single-nucleotide polymorphisms in the KITLG gene, the ligand for the cKIT tyrosine kinase receptor, as strong modifiers of susceptibility to both familial and sporadic testicular germ cell tumors.
  
  
  METHODS
  We studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds, in whom the PDE11A gene had been sequenced by investigating the association between KITLG genome-wide association study single-nucleotide polymorphisms rs3782179 and rs4474514 and FTGCT risk in these patients and in 692 controls. We also examined cAMP and c-KIT signaling in testicular tissues and cell lines and extended the studies to 2 sporadic cases, one with a PDE11A defect and one without, as a comparison.
  
  
  RESULTS
  We found a higher frequency of the KITLG risk alleles in FTGCT patients who also had a PDE11A sequence variant, compared with those with a wild-type PDE11A sequence. In NTERA-2 and Tcam-2 cells transfected with the mutated forms of PDE11A (R52T, F258Y, Y727C, R804H, V820M, R867G, and M878V), cAMP levels were significantly higher, and the relative phosphodiesterase activity was lower than in the wild-type cells. KITLG expression was consistently increased in the presence of PDE11A-inactivating defects, both at the RNA and protein levels, in familial testicular germ cell tumors. The 2 sporadic cases that were studied, one with a PDE11A defect and another without, agreed with the data in FTGTCT and in the cell lines.
  
  
  CONCLUSIONS
  Patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently. There may be an interaction between cAMP and c-KIT signaling in predisposition to testicular germ cell tumors.
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Monalisa F
authors.initials: MF
authors.lastname: Azevedo
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Bornstein
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.forename: Evgenia
authors.initials: E
authors.lastname: Gourgari
authors.forename: Kiran
authors.initials: K
authors.lastname: Nadella
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Rodrigo Bertollo
authors.initials: RB
authors.lastname: de Alexandre
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000209:etiology / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000032:analysis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000032:analysis / Q000235:genetics*; D013736:Testicular Neoplasms / Q000209:etiology / Q000235:genetics*
chemical_list: D019089:Stem Cell Factor; D000242:Cyclic AMP; D019009:Proto-Oncogene Proteins c-kit; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human