Background: Familial pituitary tumours are thought to be rare, occurring in approximately 5% of pituitary tumour cases (Tichomirowa et al. 2011). Germline mutations in MEN1, AIP, p27 and PRKAR1A are known to be involved (Elston et al. 2009), however recently SDHx and GPR101 have been added to the expanding list of genes implicated in the hereditary predisposition to pituitary tumours (Gill et al. 2014; Trivellin et al. 2014). Utilising next generation sequencing technology, we have developed a 300+ gene panel incorporating genes known to be involved in pituitary tumour pathogenesis, pituitary embryogenesis and broad cancer genes. We have commenced screening familial pituitary and young sporadic pituitary tumour cases with this panel. Using this approach, we identified a rare missense, heterozygous variant in fibroblast growth factor receptor 1 (FGFR1)(c.485A>C; p.D162A), in a male with a childhood-onset prolactinoma whose daughter has congenital hypopituitarism. Germline mutations in FGFR1 have been implicated in congenital hypopituitarism.
Aim: To determine whether the identified FGFR1 variant p.D162A is functionally deleterious using an established culture model, in vitro.
Method: Rat L6-myoblasts which contain very low levels of endogenous FGF receptors and ligands, were transfected with wild-type and mutant FGFR1 pcmv-SPORT6 expression vectors along with a luciferase reporter driven by 6 tandem repeats of the osteoblast-specific core binding sequences of the FGF responsive osteocalcin promoter (Kim et al. 2003). Cells were treated with recombinant human FGF2 ligand and then lysed for luciferase assay 24 hours later. Treatments were conducted in triplicate and cultures repeated three times.
Results:FGFR1 [p.D162A] variant exhibited a 40% reduced function (p<0.001) compared to wildtype.
Conclusion: We have identified a loss-of-function mutation in FGFR1 in a patient with a pituitary tumour. Identification of the same mutation in the daughter and in other families may also implicate FGFR1 in the hereditary predisposition to pituitary tumours.