title: Disease-modifying polymorphisms and C609Y mutation ofRETassociated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A.
abstract: Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with otherRETmutations are at higher risk of younger age onset phaeochromocytoma if they also possess otherRETpolymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation inRET. Sanger sequencing of the entireRET-coding region and exon-intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904SRETpolymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with aRETC609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening ofRETpolymorphisms for the purposes of risk stratification.
  
  
  CONCLUSIONS
  C609YRETmutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.C609YRETmutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.There may be a role for the routine screening ofRETpolymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.
authors.affiliation: Departments of Oncology and Metabolism , University of Sheffield.
authors.forename: Rowena
authors.initials: R
authors.lastname: Speak
authors.affiliation: Department of Genetics , Sheffield Children's Hospital, Sheffield , UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Cook
authors.affiliation: Endocrine Surgery , Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield , UK.
authors.forename: Barney
authors.initials: B
authors.lastname: Harrison
authors.affiliation: Departments of Oncology and Metabolism, University of Sheffield; Endocrinology.
authors.forename: John
authors.initials: J
authors.lastname: Newell-Price