Young Shin Song1, Jae-Kyung Won2, Seong-Keun Yoo3,4, Kyeong Cheon Jung2, Min Joo Kim1, Su-Jin Kim5, Sun Wook Cho1, Kyu Eun Lee3,5, Ka Hee Yi6, Jeong-Sun Seo3,4, Young Joo Park1,3. 1. 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea. 2. 2 Department of Pathology, and Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea. 3. 3 Genomic Medicine Institute, Medical Research Center; Seoul, Korea. 4. 4 Interdisciplinary Program in Bioinformatics; Seoul National University , Seoul, Korea. 5. 5 Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea. 6. 6 Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center , Seoul, Korea.
Abstract
BACKGROUND: Among subtypes of follicular variant of papillary thyroid carcinoma (FVPTC), encapsulated FVPTC (EFVPTC) shows more indolent behavior than infiltrative FVPTC (IFVPTC). In particular, noninvasive EFVPTC, now designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tends to have an excellent prognosis. However, it remains unclear whether the molecular pathogenesis or signature of the various forms of FVPTC is different. By massively parallel sequencing analysis, this study comprehensively characterized the transcriptional and mutational landscape of FVPTC and established correlations with phenotypic subtypes. METHODS: This study included 48 FVPTCs: 17 NIFTPs, 13 invasive EFVPTCs (I-EFVPTCs), and 18 IFVPTCs. For comparison, 55 classical papillary thyroid carcinomas (cPTCs) harboring a BRAFV600E mutation, six follicular adenomas (FAs), and 15 minimally invasive follicular thyroid carcinomas (miFTCs) with RAS mutations were also included. RESULTS: In NIFTP, the BRAFV600E mutation was not found, but RAS and other alterations were present in 64.7% and 17.6% of cases, respectively. However, in I-EFVPTC and IFVPTC, the proportions of BRAFV600E mutation (38.5% and 38.9%, respectively) and of RAS mutations (38.5% and 38.9%, respectively) or other alterations (15.4% and 16.7%, respectively) were similar. On a molecular level, RAS-mutated FVPTCs were all RAS-like except for one IFVPTC case. Transcriptomic profiles of NIFTP, I-EFVPTC, and FA/miFTC were comparable, although the profile of RAS-mutated IFVPTC was altered to activate molecular pathways involved in cell adhesion and invasion. Interestingly, 80% of BRAFV600E-mutated I-EFVPTCs were also classified as RAS-like, whereas all BRAFV600E-mutated IFVPTCs were BRAF-like and indistinguishable from cPTC. Molecular pathways associated with cell adhesion and invasion were also differentially activated in BRAFV600E-mutated IFVPTC. CONCLUSIONS: Molecular profiles of NIFTP and I-EFVPTC may be shared with FA/miFTC, while IFVPTC seems to be associated with a similar profile as cPTC. Activation of cell adhesion and invasion pathways may play a key role in the development of invasive phenotypes of FVPTC.
BACKGROUND: Among subtypes of follicular variant of papillary thyroid carcinoma (FVPTC), encapsulated FVPTC (EFVPTC) shows more indolent behavior than infiltrative FVPTC (IFVPTC). In particular, noninvasive EFVPTC, now designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tends to have an excellent prognosis. However, it remains unclear whether the molecular pathogenesis or signature of the various forms of FVPTC is different. By massively parallel sequencing analysis, this study comprehensively characterized the transcriptional and mutational landscape of FVPTC and established correlations with phenotypic subtypes. METHODS: This study included 48 FVPTCs: 17 NIFTPs, 13 invasive EFVPTCs (I-EFVPTCs), and 18 IFVPTCs. For comparison, 55 classical papillary thyroid carcinomas (cPTCs) harboring a BRAFV600E mutation, six follicular adenomas (FAs), and 15 minimally invasive follicular thyroid carcinomas (miFTCs) with RAS mutations were also included. RESULTS: In NIFTP, the BRAFV600E mutation was not found, but RAS and other alterations were present in 64.7% and 17.6% of cases, respectively. However, in I-EFVPTC and IFVPTC, the proportions of BRAFV600E mutation (38.5% and 38.9%, respectively) and of RAS mutations (38.5% and 38.9%, respectively) or other alterations (15.4% and 16.7%, respectively) were similar. On a molecular level, RAS-mutated FVPTCs were all RAS-like except for one IFVPTC case. Transcriptomic profiles of NIFTP, I-EFVPTC, and FA/miFTC were comparable, although the profile of RAS-mutated IFVPTC was altered to activate molecular pathways involved in cell adhesion and invasion. Interestingly, 80% of BRAFV600E-mutated I-EFVPTCs were also classified as RAS-like, whereas all BRAFV600E-mutated IFVPTCs were BRAF-like and indistinguishable from cPTC. Molecular pathways associated with cell adhesion and invasion were also differentially activated in BRAFV600E-mutated IFVPTC. CONCLUSIONS: Molecular profiles of NIFTP and I-EFVPTC may be shared with FA/miFTC, while IFVPTC seems to be associated with a similar profile as cPTC. Activation of cell adhesion and invasion pathways may play a key role in the development of invasive phenotypes of FVPTC.
Authors: David C Shonka; Alan Ho; Ashish V Chintakuntlawar; Jessica L Geiger; Jong C Park; Nagashree Seetharamu; Sina Jasim; Amr H Abdelhamid Ahmed; Keith C Bible; Marcia S Brose; Maria E Cabanillas; Kirsten Dabekaussen; Louise Davies; Dora Dias-Santagata; James A Fagin; William C Faquin; Ronald A Ghossein; Raj K Gopal; Akira Miyauchi; Yuri E Nikiforov; Matthew D Ringel; Bruce Robinson; Mabel M Ryder; Eric J Sherman; Peter M Sadow; Jennifer J Shin; Brendan C Stack; R Michael Tuttle; Lori J Wirth; Mark E Zafereo; Gregory W Randolph Journal: Head Neck Date: 2022-03-11 Impact factor: 3.821
Authors: Sina Dadafarin; Tomás C Rodríguez; Michelle A Carnazza; Raj K Tiwari; Augustine Moscatello; Jan Geliebter Journal: Cells Date: 2022-10-10 Impact factor: 7.666