Oral Presentation ESA-SRB Conference 2015

Loss-of-function germline FGFR1 mutation identified in a patient with prolactinoma (#191)

Mark J McCabe 1 2 , Anthony R Lam 2 3 , Tanya J Thompson 4 5 , Marcel E Dinger 1 2 , Ann I McCormack 4 6
  1. St Vincent’s Clinical School, UNSW Australia, Sydney, NSW, Australia
  2. The Kinghorn Centre for Clinical Genomics and Hormones and Cancer group, Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
  4. Hormones and Cancer, Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  5. Department of Endocrinology, St Vincent's Hospital, Darlinghurst, NSW, Australia
  6. Hormones and Cancer, Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

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.

  1. Elston et al. Familial pituitary tumor syndromes. Nat Rev Endocrinol 2009;5:453-461.
  2. Gill et al. Succinate dehydrogenase deficiency is rare in pituitary adenomas. Am J Surg Pathol 2014;38:560-566.
  3. Kim et al. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem 2003;278:319-326.
  4. Tichomirowa et al. High prevalence of AIP mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol 2011;165:509-515.
  5. Trivellin et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014;371:2363-2674.