title: Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations.
abstract: BACKGROUND
  Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy.
  
  
  METHODS
  From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed.
  
  
  RESULTS
  236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels (p<0.0001). Patients with a codon 620 mutation were 2.8-6.9 times more likely to have MTC than other level B mutation carriers, and 5.1-21.7 times more likely than level A mutation carriers included in our focus population. The youngest median time to MTC was 19 years for codon 620 and the oldest was 56 years for codon 611. Cumulative prevalence of MTC by age 20 was 10% or lower for codons 533, 609, 611, 791, and 804. By age 50, it ranged from 18% for codon 791 to 95% for codon 620. An elevated preoperative calcitonin level strongly predicted MTC on final pathology, though false-negative rates varied by codon (p<0.0001). Positive predictive values ranged from 76% to 100% by codon with an overall positive predictive value of 87% across codons.
  
  
  CONCLUSIONS
  This study offers a better understanding of the age-related development of MTC in lower risk RET mutation carriers, provides evidence of further distinctions between lower risk mutations within ATA subgroups, and clarifies the clinical significance of codon 791 mutations. The data support individualized "codon-based" management approaches coupled with clinical data such as calcitonin levels.
authors.affiliation: 1 Department of Surgical Oncology, MD Anderson Cancer Center, University of Texas , Houston, Texas.
authors.forename: Thereasa A
authors.initials: TA
authors.lastname: Rich
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Naifa
authors.initials: N
authors.lastname: Busaidy
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Cote
authors.forename: Robert F
authors.initials: RF
authors.lastname: Gagel
authors.forename: Mimi
authors.initials: M
authors.lastname: Hu
authors.forename: Camilo
authors.initials: C
authors.lastname: Jimenez
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: Nancy
authors.initials: N
authors.lastname: Perrier
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
authors.forename: Steven G
authors.initials: SG
authors.lastname: Waguespack
authors.forename: Anita
authors.initials: A
authors.lastname: Ying
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grubbs
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012306:Risk; D013964:Thyroid Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human