Oral Presentation ESA-SRB Conference 2015

Germline mutation in the MET proto-oncogene, receptor tyrosine kinase/hepatocyte growth factor receptor (MET) in a patient with phaeochromocytoma – a new gene for this disorder (#193)

Jessica E Harris 1 , Aidan Flynn 2 3 , Aideen M McInerney-Leo 1 , Janelle McFarlene 1 , Mhairi S Marshall 1 , Matthew A Brown 1 , Anthony J Gill 4 5 , Paul J Leo 1 , Richard W Tothill 2 3 , Rod Hicks 2 3 , Roderick J Clifton-Bligh 4 6 , Emma L Duncan 1 7 8
  1. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
  2. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. The Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
  4. University of Sydney, Sydney, NSW
  5. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, , Royal North Shore Hospital , Sydney, NSW, Australia
  6. Cancer Genetics, Kolling Institute of Medical Research, Sydney, NSW, Australia
  7. Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australai
  8. School of Medicine, Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Phaeochromocytomas (PCC) and paragangliomas (PGL) are heritable neuroendocrine tumours arising in the adrenal medulla and/or extra-adrenal paraganglia tissue. Germline mutations in one of 16 identified susceptibility genes are detected in up to 40% of PCC/PGL patients; additionally, somatic mutations are found in a further 30%. However, in some cases the genetic aetiology of the tumour remains unknown.

Whole exome sequencing was performed on germline DNA from a proband with PCC and a highly suggestive family history. No variants were detected in known PCC/PGL susceptibility genes. A rare heterozygous missense variant (c.3272C>T, p.Pro1091Leu) was identified in the tyrosine kinase domain of the MET proto-oncogene receptor tyrosine kinase/hepatocyte growth factor receptor predicted to be damaging by in silico prediction tools. No unaffected family members carried this variant; unfortunately there were no surviving family members with suspected PCC to confirm segregation. Consistent with oncogenic MET activation, gene expression profiling classified the tumour as a subtype of PCC associated with RET and NF1 mutations, supporting a genotype associated with activated kinase signalling.

Germline mutations in the tyrosine kinase domain of MET have been reported in hereditary papillary renal cell carcinoma (RCC). Our case emphasizes the similarities between heritable PCC/PGL and RCC, evidenced by FH, VHL, and SDHx known to confer susceptibility to both. Moreover, PCC/PGL susceptibility genes are frequent targets for somatic mutation in sporadic tumours: somatic MET mutations in PCC have recently been reported, further supporting our proposition that this case is the first description of a new heritable form of PCC. Finally, we recently identified a second individual with a germline MET variant (awaiting Sanger sequencing validation).

We suggest that MET should be included in genetic testing of PCC cases and their families. Whether our case is at risk for RCC, and conversely whether hereditary MET-associated RCC are at risk for PCC, remains to be determined.