title: RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China.
abstract: BACKGROUND
  Genetic screening for germline mutations in the RET proto-oncogene has been extensively exploited worldwide to optimize the diagnostic and clinical management of multiple endocrine neoplasia type 2 (MEN2) patients and their relatives. However, a distinct lag period exists not only in the recognition but also in the medical treatment of patients with MEN2. Here we present a comprehensive genetic and clinical analysis of MEN2 among Chinese families followed from 1975 to 2011. Our series comprises 36 index cases and 134 relatives from 11 independent families.
  
  
  METHODS
  Genetic diagnosis was performed in all participants by direct sequencing all relevant RET exons. Thyroidectomy was performed in 50 patients with varying cervical neck dissection procedures. Patients with pheochromocytoma (PHEO) underwent specific surgery. Demographic, clinical profiles, mutation types, tumor histopathologic features, and follow-up records were systematically analyzed.
  
  
  RESULTS
  The RET mutations p.C634Y (n=34), p.C634R (n=6), p.C618S (n=13), p.V292M/R67H/R982C (n=7), p.L790F (n=2), and p.C634Y/V292M/R67H/R982C (n=1) were confirmed in 31 index cases and then identified in 32 at-risk relatives (mutation carriers), with MEN2A as the most common clinical subtype. The overall penetrance of PHEO in patients with MEN2A was 46.7%. A total of 50 patients underwent thyroidectomy, and there was a significant lowering of their mean age at thyroidectomy and the tumor diameter of the mutation carriers that were detected and operated on compared with the index cases (age at first surgery: 29.3 vs. 39.3 years, p<0.05; maximum size: 1.1 vs. 3.3 cm, p<0.001). There was also a decrease in the TNM staging and the proportion of patients who underwent inappropriate initial thyroid surgery (pN1: 31.6% vs. 100%, p<0.001; inappropriate surgery: 0% vs. 29%). Meanwhile, disease-free survival (DFS) increased (DFS: 100% vs. 58.1%, p<0.05). Both medullary thyroid carcinoma-specific (n=1) and PHEO-specific (n=5) deaths were reported during the study period.
  
  
  CONCLUSIONS
  Our results further substantiate that gene scanning of all relevant RET exons is a powerful tool in the management of MEN2 patients, especially in asymptomatic carriers, and has led to earlier diagnosis and more complete initial treatment of patients with MEN2 in China.
authors.affiliation: Department of Oncologic Surgery, The 117th PLA Hospital, Hangzhou, China. qxplmd@163.com
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Qi
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Chen
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Ma
authors.forename: Zhen-Fang
authors.initials: ZF
authors.lastname: Du
authors.forename: Jun
authors.initials: J
authors.lastname: Fei
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Qi-Zhe
authors.initials: QZ
authors.lastname: Song
authors.forename: Jian-Shan
authors.initials: JS
authors.lastname: Han
authors.forename: Hang-Yang
authors.initials: HY
authors.lastname: Jin
authors.forename: Zhen-Guang
authors.initials: ZG
authors.lastname: Chen
authors.forename: Jin-Quan
authors.initials: JQ
authors.lastname: Wang
authors.forename: You-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Rong-Biao
authors.initials: RB
authors.lastname: Ying
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Chun-Yue
authors.initials: CY
authors.lastname: Chen
authors.forename: Hu-Ling
authors.initials: HL
authors.lastname: Jiang
authors.forename: Hai-Ping
authors.initials: HP
authors.lastname: Ke
authors.forename: Xian-Ning
authors.initials: XN
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000601:surgery; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D010673:Pheochromocytoma / Q000601:surgery; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011519:Proto-Oncogenes; D013964:Thyroid Neoplasms / Q000601:surgery; D013965:Thyroidectomy
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human