RET Proto-Oncogene Genetic Screening of Families with Multiple Endocrine Neoplasia Type 2 Optimizes Diagnostic and Clinical Management in China.

Qi XP, Chen XL, Ma JM, Du ZF, Fei J, Yang CP, Cheng J, Song QZ, Han JS, Jin HY, Chen ZG, Wang JQ, Yang YP, Ying RB, Liu WT, Zhao Y, Chen CY, Jiang HL, Ke HP, Zhang XN.

Source

1 Departments of Oncologic Surgery, Urologic Surgery, and Pathology, and Clinical Experimental Center, The 117th PLA Hospital , Hangzhou, 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=".05" 0="0" 1.1="1.1" 100="100" 29="29" 3.3="3.3" 31.6="31.6" 58.1="58.1" a="a" all="all" also="also" and="and" asymptomatic="asymptomatic" both="both" carcinoma-specific="carcinoma-specific" carriers="carriers" china.="china." cm="cm" complete="complete" conclusions:="conclusions:" deaths="deaths" decrease="decrease" diagnosis="diagnosis" disease-free="disease-free" during="during" earlier="earlier" especially="especially" exons="exons" further="further" gene="gene" has="has" in="in" inappropriate="inappropriate" increased="increased" initial="initial" is="is" led="led" management="management" maximum="maximum" meanwhile="meanwhile" medullary="medullary" men2="men2" more="more" n="5)" of="of" our="our" p="p" patients="patients" period.="period." pheo-specific="pheo-specific" pn1:="pn1:" powerful="powerful" proportion="proportion" relevant="relevant" reported="reported" results="results" ret="ret" scanning="scanning" size:="size:" staging="staging" study="study" substantiate="substantiate" surgery:="surgery:" surgery="surgery" survival="survival" that="that" the="the" there="there" thyroid="thyroid" tnm="tnm" to="to" tool="tool" treatment="treatment" underwent="underwent" vs.="vs." was="was" were="were" who="who" with="with">