Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

被引：22

作者：

Xu, Bin ^{[1
]}

Viswanathan, Kartik ^{[4
]}

Ahadi, Mahsa S. ^{[5
,6
,7
,8
]}

Ahmadi, Sara ^{[9
]}

Alzumaili, Bayan ^{[1
]}

Bani, Mohamed-Amine ^{[11
]}

Baudin, Eric ^{[12
]}

Behrman, David Blake ^{[4
]}

Capelletti, Marzia ^{[10
]}

Chau, Nicole G. ^{[10
]}

Chiarucci, Federico ^{[13
]}

Chou, Angela ^{[5
,6
,7
,8
]}

Clifton-Bligh, Roderick ^{[5
,6
,7
,8
]}

Coluccelli, Sara ^{[13
]}

de Biase, Dario ^{[14
]}

De Leo, Antonio ^{[13
]}

Dogan, Snjezana ^{[1
]}

Fagin, James A. ^{[2
]}

Fuchs, Talia L. ^{[5
,6
,7
,8
]}

Glover, Anthony Robert ^{[5
,6
]}

Hadoux, Julien ^{[12
]}

Lacroix, Ludovic ^{[11
]}

Lamartina, Livia ^{[12
]}

Lubin, Daniel J. ^{[4
]}

Luxford, Catherine ^{[5
,6
,7
,8
]}

Magliocca, Kelly ^{[4
]}

Maloberti, Thais ^{[13
]}

Mohanty, Abhinita S. ^{[1
]}

Najdawi, Fedaa ^{[10
]}

Nigam, Aradhya ^{[3
]}

Papachristos, Alexander James ^{[5
,6
,7
,8
]}

Repaci, Andrea ^{[15
]}

Robinson, Bruce ^{[5
,6
,7
,8
]}

Scoazec, Jean-Yves ^{[11
]}

Shi, Qiuying ^{[4
]}

Sidhu, Stan ^{[5
,6
,7
,8
]}

Solaroli, Erica ^{[16
]}

Sywak, Mark ^{[5
,6
,7
,8
]}

Tuttle, R. Michael ^{[2
]}

Untch, Brian ^{[3
]}

Barletta, Justine A. ^{[10
]}

Al Ghuzlan, Abir ^{[11
]}

Gill, Anthony J. ^{[5
,6
,7
,8
]}

Ghossein, Ronald ^{[1
,17
]}

Tallini, Giovanni ^{[13
]}

Ganly, Ian ^{[3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Pathol & Lab Med, New York, NY USA

[2] Mem Sloan Kettering Canc Ctr, Div Specialized Med, New York, NY USA

[3] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY USA

[4] Emory Univ, Dept Pathol, Hosp Midtown, Atlanta, GA USA

[5] Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia

[6] Univ Sydney, Northern Clin Sch, Sydney Med Sch, Sydney, NSW, Australia

[7] Royal North Shore Hosp, Kolling Inst Med Res, Canc Diag & Pathol Grp, St Leonards, NSW, Australia

[8] Royal North Shore Hosp, Dept Anat Pathol, NSW Hlth Pathol, St Leonards, NSW, Australia

[9] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Endocrinol & Metab, Boston, MA USA

[10] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[11] Gustave Roussy Campus Canc, Med Pathol & Biol Dept, Serv Oncol Endocrinienne, Villejuif, France

[12] Gustave Roussy Campus Canc, Dept Imagerie, Serv Oncol Endocrinienne, Villejuif, France

[13] Univ Bologna, Med Ctr, Dept Med & Surg Sci DIMEC, Bologna, Italy

[14] Univ Bologna, Dept Pharm & Biotechnol, IRCCS Azienda Osped, Bologna, Italy

[15] Univ Bologna, Div Endocrinol & Diabet Prevent & Care, IRCCS Azienda Osped, Bologna, Italy

[16] Azienda USL Bologna, Endocrinol Unit, Bologna, Italy

[17] Mem Sloan Kettering Canc Ctr, Dept Pathol & Lab Med, 1275 York Ave, New York, NY 10065 USA

来源：

THYROID | 2024年 / 34卷 / 02期

关键词：

medullary thyroid carcinoma; grade; RET; RAS; prognosis; RET PROTOONCOGENE MUTATIONS; RAS MUTATIONS; LOW-PREVALENCE; CANCER; PHENOTYPE; ASSAY; KI-67;

D O I：

10.1089/thy.2023.0279

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

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.

引用

页码：167 / 176

页数：10

共 39 条

[1] Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS [J].

Agrawal, Nishant ;

Jiao, Yuchen ;

Sausen, Mark ;

Leary, Rebecca ;

Bettegowda, Chetan ;

Roberts, Nicholas J. ;

Bhan, Sheetal ;

Ho, Allen S. ;

Khan, Zubair ;

Bishop, Justin ;

Westra, William H. ;

Wood, Laura D. ;

Hruban, Ralph H. ;

Tufano, Ralph P. ;

Robinson, Bruce ;

Dralle, Henning ;

Toledo, Sergio P. A. ;

Toledo, Rodrigo A. ;

Morris, Luc G. T. ;

Ghossein, Ronald A. ;

Fagin, James A. ;

Chan, Timothy A. ;

Velculescu, Victor E. ;

Vogelstein, Bert ;

Kinzler, Kenneth W. ;

Papadopoulos, Nickolas ;

Nelkin, Barry D. ;

Ball, Douglas W. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2013, 98 (02) :E364-E369

[2] Grading of medullary thyroid carcinoma on the basis of tumor necrosis and high mitotic rate is an independent predictor of poor outcome [J].

Alzumaili, Bayan ;

Xu, Bin ;

Spanheimer, Philip M. ;

Tuttle, R. Michael ;

Sherman, Eric ;

Katabi, Nora ;

Dogan, Snjezana ;

Ganly, Ian ;

Untch, Brian R. ;

Ghossein, Ronald A. .

MODERN PATHOLOGY, 2020, 33 (09) :1690-1701

[3] Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations [J].

Barletta, Justine A. ;

Nose, Vania ;

Sadow, Peter M. .

ENDOCRINE PATHOLOGY, 2021, 32 (01) :35-43

[4] Somatic RAS Mutations Occur in a Large Proportion of Sporadic RET-Negative Medullary Thyroid Carcinomas and Extend to a Previously Unidentified Exon [J].

Boichard, A. ;

Croux, L. ;

Al Ghuzlan, A. ;

Broutin, S. ;

Dupuy, C. ;

Leboulleux, S. ;

Schlumberger, M. ;

Bidart, J. M. ;

Lacroix, L. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (10) :E2031-E2035

[5] Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].

Cheng, Donavan T. ;

Mitchell, Talia N. ;

Zehir, Ahmet ;

Shah, Ronak H. ;

Benayed, Ryma ;

Syed, Aijazuddin ;

Chandramohan, Raghu ;

Liu, Zhen Yu ;

Won, Helen H. ;

Scott, Sasinya N. ;

Brannon, A. Rose ;

O'Reilly, Catherine ;

Sadowska, Justyna ;

Casanova, Jacklyn ;

Yannes, Angela ;

Hechtman, Jaclyn F. ;

Yao, Jinjuan ;

Song, Wei ;

Ross, Dara S. ;

Oultache, Alifya ;

Dogan, Snjezana ;

Borsu, Laetitia ;

Hameed, Meera ;

Nafa, Khedoudja ;

Arcila, Maria E. ;

Ladanyi, Marc ;

Berger, Michael F. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264

[6] Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing [J].

Ciampi, Raffaele ;

Romei, Cristina ;

Ramone, Teresa ;

Prete, Alessandro ;

Tacito, Alessia ;

Cappagli, Virginia ;

Bottici, Valeria ;

Viola, David ;

Torregrossa, Liborio ;

Ugolini, Clara ;

Basolo, Fulvio ;

Elisei, Rossella .

ISCIENCE, 2019, 20 :324-+

[7] Evidence of a Low Prevalence of RAS Mutations in a Large Medullary Thyroid Cancer Series [J].

Ciampi, Raffaele ;

Mian, Caterina ;

Fugazzola, Laura ;

Cosci, Barbara ;

Romei, Cristina ;

Barollo, Susi ;

Cirello, Valentina ;

Bottici, Valeria ;

Marconcini, Giulia ;

Rosa, Pelizzo Maria ;

Borrello, Maria Grazia ;

Basolo, Fulvio ;

Ugolini, Clara ;

Materazzi, Gabriele ;

Pinchera, Aldo ;

Elisei, Rossella .

THYROID, 2013, 23 (01) :50-57

[8] Molecular Diagnostic of Solid Tumor Using a Next Generation Sequencing Custom-Designed Multi-Gene Panel [J].

de Biase, Dario ;

Acquaviva, Giorgia ;

Visani, Michela ;

Sanza, Viviana ;

Argento, Chiara M. ;

De Leo, Antonio ;

Maloberti, Thais ;

Pession, Annalisa ;

Tallini, Giovanni .

DIAGNOSTICS, 2020, 10 (04)

[9] Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer:: A 10-year follow-up study [J].

Elisei, Rossella ;

Cosci, Barbara ;

Romei, Cristina ;

Bottici, Valeria ;

Renzini, Giulia ;

Molinaro, Eleonora ;

Agate, Laura ;

Vivaldi, Agnese ;

Faviana, Pinuccia ;

Basolo, Fulvio ;

Miccoli, Paolo ;

Berti, Piero ;

Pacini, Furio ;

Pinchera, Aldo .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (03) :682-687

[10] Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations [J].

Elisei, Rossella ;

Tacito, Alessia ;

Ramone, Teresa ;

Ciampi, Raffaele ;

Bottici, Valeria ;

Cappagli, Virginia ;

Viola, David ;

Matrone, Antonio ;

Lorusso, Loredana ;

Valerio, Laura ;

Giani, Carlotta ;

Campopiano, Cristina ;

Prete, Alessandro ;

Agate, Laura ;

Molinaro, Eleonora ;

Romei, Cristina .

GENES, 2019, 10 (09)

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