The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

A novel paraganglioma syndrome driven by both germline and somatic mutation (#210)

Sunita MC De Sousa 1 2 3 , Jinghua Feng 4 , Andreas W Schreiber 4 5 , Hamish S Scott 2 3 4 5 6 , David J Torpy 1 3
  1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  2. Molecular Pathology Research Laboratory, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia
  3. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  4. ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia
  5. School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
  6. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia

Introduction: Following the well-established association between succinate dehydrogenase (SDH) deficiency and PGL, SDHA/B/C/D mutations have been associated with paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumour (GIST) and pituitary adenoma (PA).1,2 Some individuals/families have developed more than one tumour;3,4 however, no family has been reported with all tumours. A subset of phaeochromocytoma/PGL associated with germline SDHB mutations harbour somatic ATRX variants, suggesting digenic models of SDH-deficient tumorigenesis.5

Methods: A kindred presented with head and neck PGL in two siblings, GIST in a third sibling and macroprolactinoma in the fourth sibling. Their mother died from RCC. Despite loss of normal SDHB immunostaining in the PGL specimens, routine genetic testing of SDHB/C/D/AF2, as well as RET, VHL and TMEM127 failed to identify causative mutations. We performed in-house whole exome sequencing (WES) using germline DNA from the four siblings and tumour DNA from PGL and GIST formalin-fixed, paraffin-embedded specimens.  

Results: WES yielded 199 germline variants that were: rare (<1% population); heterozygous in each sibling (consistent with autosomal dominant inheritance); likely damaging (by in silico analysis); and of high quality and depth of coverage (>30x). These included a novel deep intronic SDHC variant predicted to generate an alternate splice donor site with downstream frameshift, and a novel missense variant in PTCH2, a gene implicated in nevoid basal cell carcinoma syndrome (‘Gorlin’s syndrome’). Transcriptome analysis of whole blood by RNA-Seq is underway to confirm altered SDHC expression and to evaluate other candidate variants. Using similar filtration, we identified 437 somatic variants with involvement of known PGL- and GIST-predisposing genes, raising the possibility of multigenic tumorigenesis pathways.

Conclusions: The highly penetrant coexistence of PGL, RCC, GIST, PA and a novel segregating SDHC mutation describes a new paraganglioma syndrome, with possible contributions from germline and somatic variants in other genes.   

  1. Evenepoel L, Papathomas TG, Krol N, Korpershoek E, De Krijger RR, Persu A, Dinjens WN. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015 Aug;17(8):610.
  2. De Sousa SM, McCabe MJ, Wu K, Roscioli T, Gayevskiy V, Brook K, Rawlings L, Scott HS, Thompson TJ, Earls P, Gill AJ. Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours. Eur J Endocrinol. 2017 May 1;176(5):635-44.
  3. Niemeijer ND, Papathomas TG, Korpershoek E, De Krijger RR, Oudijk L, Morreau H, Bayley JP, Hes FJ, Jansen JC, Dinjens WN, Corssmit EP. Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. J Clin Endocrinol Metab. 2015 Oct 1;100(10):E1386-93.
  4. Benn DE, Robinson BG, Clifton-Bligh RJ. 15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1–5. Endocr Relat Cancer. 2015 Aug 1;22(4):T91-103.
  5. Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, LiVolsi V. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140.