Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

中文翻译：

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国际多中心研究中甲状腺髓样癌的基因组谱与肿瘤特征和临床结果的关联。

目的：需要澄清 RET 和 RAS 突变的预后重要性及其与甲状腺髓样癌 (MTC) 临床病理参数和结果的关系。实验设计：利用 290 名 MTC 患者的数据进行了一项多中心回顾性队列研究。确定分子谱并检查与临床病理数据和结果的关联。结果：40 名患者（16.3%）检测到 RET 种系突变。体细胞 RET 和 RAS 突变分别发生在 135 名 (46.9%) 和 57 名 (19.8%) 患者中。RETM918T 是最常见的体细胞 RET 突变 (n = 75)。RET 体细胞突变与男性、较大的肿瘤大小、美国癌症联合委员会 (AJCC) 分期晚期、血管侵犯和国际甲状腺髓样癌分级系统 (IMTCGS) 高分级相关。与其他 RET 体细胞突变相比，RETM918T 与年轻、AJCC（第八版）IV、血管侵犯、甲状腺外扩展和阳性切缘相关。单变量分析表明，RET 体细胞或种系突变与远处无转移生存率降低显着相关，但在调整肿瘤分级和分期后，多变量分析中不存在显着的独立关联。RET 体细胞突变和 RET 种系突变之间，或者 RETM918T 和其​​他 RET 突变之间的结果没有显着差异。其他复发性分子改变包括 TP53 (4.2%)、ARID2 (2.9%)、SETD2 (2.9%)、KMT2A (2.9%) 和 KMT2C (2.9%)。其中，TP53 突变与总生存期 (OS) 和疾病特异性生存期 (DSS) 降低相关，与肿瘤分级和 AJCC 分期无关。结论：RET 体细胞突变与高级别、侵袭性原发肿瘤特征相关，并降低无远处转移生存率，但在考虑肿瘤级别和疾病分期后，这种关系并不显着。RETM918T 与侵袭性原发肿瘤相关，但与临床结果不独立相关。TP53 突变可能代表与 MTC 中 OS 和 DSS 降低相关的不良分子事件，但其预后价值需要在未来的研究中得到证实。