Suteau Valentine, Lebeault Maÿlis, Schlumberger Martin, Zalzali Mohamed, Lasolle Hélène, Le Bras Maëlle, Chabrier Gérard, Raingeard Isabelle, Castinetti Frédéric, Caron Philippe, Ghander Cécile, Chevalier Nicolas, Mirebeau-Prunier Delphine, Rohmer Vincent, Rodien Patrice, Briet Claire
CHU d'Angers, Service d'Endocrinologie-Diabétologie-Nutrition, 4, rue Larrey, 49100 Angers, France.
Institut Gustave-Roussy, Service de Médecine Nucléaire, 94800 Villejuif, France.
Ann Endocrinol (Paris). 2025 Apr;86(2):101705. doi: 10.1016/j.ando.2025.101705. Epub 2025 Jan 20.
RET variants affecting codon 804 are part of the low-to-moderate risk group in the ATA classification, with indications for prophylactic thyroidectomy beyond age of 5years. However, aggressiveness seems to be variable. The objective of this study was to report a large cohort of French carriers of a pathogenic variant at codon 804 in the RET proto-oncogene.
Patients from 12 university hospitals with a RET 804 variant were recruited in this retrospective non-interventional French national study, from the French GTE-ENDOCAN-RENATEN database. Incidence and severity (TNM stage and calcitonin levels) of medullary thyroid carcinoma (MTC), phenotype-genotype correlation and clinical outcome were assessed.
A total of 322 patients were analyzed. Index cases (n=65) had a median age at diagnosis of 57years (range: 46-66), and relatives (n=257) a median age of 37years (range: 18-51). Median first calcitonin measurement was 240ng/L (range: 79-1344) in index cases, and 6.7ng/L (range: 0-22) in relatives. In index cases, the pathogenic variant c.2410G>A (p.Val804Met) in RET was more frequent (80% of cases) than c.2410G>C or c.2410G>T (p.Val804Leu). MTC was multifocal, node-positive and metastatic in 64%, 51% and 20% of cases respectively. TNM stage, preoperative calcitonin level and male gender were predictive of persistent disease (defined by postoperative calcitonin>5ng/L) (P<0.001). Ten-year disease-free survival (DFS) was 61%. In total, 113 relatives were operated on: 62% with MTC and 34% with isolated C-cell hyperplasia (CCH); the youngest patients were aged 20 for MTC and 4years for CCH. Ten-year DFS was 90%.
The RET pathogenic variants affecting the codon 804 mainly led to low aggressiveness disease, with late presentation and prolonged DFS. We suggest surgery in relatives if calcitonin values are above 6ng/L, instead of 10ng/L. Long-term surveillance is mandatory, since recurrence remains possible several years after surgery.
影响第804密码子的RET变异体属于ATA分类中低至中度风险组，有指征在5岁以后进行预防性甲状腺切除术。然而，侵袭性似乎存在差异。本研究的目的是报告一大群法国RET原癌基因第804密码子致病性变异体携带者。
在这项回顾性非干预性法国全国性研究中，从法国GTE-ENDOCAN-RENATEN数据库招募了来自12家大学医院的携带RET 804变异体的患者。评估甲状腺髓样癌（MTC）的发病率和严重程度（TNM分期和降钙素水平）、表型-基因型相关性及临床结局。
共分析了322例患者。索引病例（n=65）诊断时的中位年龄为57岁（范围：46-66岁），亲属（n=257）的中位年龄为37岁（范围：18-51岁）。索引病例首次降钙素测量的中位数为240ng/L（范围：79-1344），亲属为6.7ng/L（范围：0-22）。在索引病例中，RET基因致病性变异c.2410G>A（p.Val804Met）比c.2410G>C或c.2410G>T（p.Val804Leu）更常见（80%的病例）。MTC分别在64%、51%和20%的病例中为多灶性、有淋巴结转移和远处转移。TNM分期、术前降钙素水平和男性性别可预测持续性疾病（定义为术后降钙素>5ng/L）（P<0.001）。10年无病生存率（DFS）为61%。共有113名亲属接受了手术：62%患有MTC，34%患有孤立性C细胞增生（CCH）；MTC最年轻的患者为20岁，CCH为4岁。10年DFS为90%。
影响第804密码子的RET致病性变异体主要导致侵袭性较低的疾病，发病较晚，DFS延长。我们建议，如果降钙素值高于6ng/L而不是10ng/L，亲属应接受手术。由于术后数年仍可能复发，长期监测是必要的。
