作者
Bin Xu,Kartik Viswanathan,Mahsa Ahadi,Sara Ahmadi,Bayan Alzumaili,Mohamed Amine Bani,Éric Baudin,David Behrman,Marzia Capelletti,Nicole G. Chau,Federico Chiarucci,Angela Chou,Roderick Clifton‐Bligh,Sara Coluccelli,Dario de Biase,Antonio De Leo,Snjezana Doğan,James A. Fagin,Talia L Fuchs,Anthony Glover,Julien Hadoux,Ludovic Lacroix,Livia Lamartina,Daniel Lubin,Catherine Luxford,Kelly R. Magliocca,Thais Maloberti,Abhinita Mohanty,Fedaa Najdawi,Aradhya Nigam,Alexander Papachristos,Andrea Repaci,Bruce G. Robinson,Jean‐Yves Scoazec,Qiuying Shi,Stan Sidhu,Erica Solaroli,Mark Sywak,R. Michael Tuttle,Brian R. Untch,Justine A. Barletta,Abir Al Ghuzlan,Anthony J. Gill,Ronald Ghossein,Giovanni Tallini,Ian Ganly
摘要
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.