title: Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours.
abstract: OBJECTIVE
  Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel.
  
  
  METHODS
  We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion forMEN1,CDKN1BandAIPmutations. The main outcomes were frequency and pathogenicity of rare variants inAIP,CDKN1B,MEN1,PRKAR1A,SDHA,SDHB,SDHCandSDHD.
  
  
  RESULTS
  Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested:AIP(p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W),MEN1(p.R176Q),SDHB(p.A2V, p.S8S),SDHC(p.E110Q) andSDHD(p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified inMEN1,CDKN1BorAIP.
  
  
  CONCLUSIONS
  A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.
authors.affiliation: Hormones and Cancer GroupGarvan Institute of Medical Research, Sydney, Australia.|Endocrine and Metabolic UnitRoyal Adelaide Hospital, Adelaide, Australia.|Department of Genetics and Molecular PathologyCentre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, Australia.|School of MedicineUniversity of Adelaide, Adelaide, Australia.
authors.forename: Sunita M C
authors.initials: SMC
authors.lastname: De Sousa
authors.affiliation: Hormones and Cancer GroupGarvan Institute of Medical Research, Sydney, Australia.|Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical SchoolUniversity of New South Wales, Sydney, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McCabe
authors.affiliation: Familial Cancer ServiceWestmead Hospital, Westmead, Australia.|School of MedicineUniversity of Sydney, Sydney, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Wu
authors.affiliation: Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical SchoolUniversity of New South Wales, Sydney, Australia.|Department of Medical GeneticsSydney Children's Hospital, Sydney, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.affiliation: Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical Research, Sydney, Australia.
authors.forename: Velimir
authors.initials: V
authors.lastname: Gayevskiy
authors.affiliation: Department of Genetics and Molecular PathologyCentre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, Australia.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Brook
authors.affiliation: Department of Genetics and Molecular PathologyCentre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Rawlings
authors.affiliation: Department of Genetics and Molecular PathologyCentre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, Australia.|School of MedicineUniversity of Adelaide, Adelaide, Australia.|ACRF Cancer Genomics FacilityCentre for Cancer Biology, SA Pathology, Adelaide, Australia.|School of Biological SciencesUniversity of Adelaide, Adelaide, Australia.|School of Pharmacy and Medical SciencesUniversity of South Australia, Adelaide, Australia.
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.affiliation: Hormones and Cancer GroupGarvan Institute of Medical Research, Sydney, Australia.
authors.forename: Tanya J
authors.initials: TJ
authors.lastname: Thompson
authors.affiliation: School of Pharmacy and Medical SciencesUniversity of South Australia, Adelaide, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Earls
authors.affiliation: School of MedicineUniversity of Sydney, Sydney, Australia.|Cancer Diagnosis and Pathology GroupKolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.|Sydney Vital Translational Cancer Research CentreRoyal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical SchoolUniversity of New South Wales, Sydney, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical SchoolUniversity of New South Wales, Sydney, Australia.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Dinger
authors.affiliation: Hormones and Cancer GroupGarvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical SchoolUniversity of New South Wales, Sydney, Australia.|Department of EndocrinologySt Vincent's Hospital, Sydney, Australia.
authors.forename: Ann I
authors.initials: AI
authors.lastname: McCormack
mesh_terms: D000328:Adult; D001315:Australia / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000235:genetics*; D003430:Cross-Sectional Studies; D004701:Endocrine Gland Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D010911:Pituitary Neoplasms / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor