Molecular profile of Hurthle cell carcinomas: recurrent mutations in the Wnt/beta-caten n pathway

Author(s)

Santana, Nathalie Oliveira ^[1] ; Lerario, Antonio Marcondes ^[2] ; Schmerling, Claudia Kliemann ^[3] ; Marui, Suemi ^[1] ; Ferreira Alves, Venancio Avancini ^[3] ; Hoff, Ana O. ^[4] ; Kopp, Peter ^{[5, 6]} ; Seguro Danilovic, Debora Lucia ^{[1, 4]}

Affiliation

^[1] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Lab Endocrinol Celular & Mol LIM25, Sao Paulo - Brazil

^[2] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[3] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Pathol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Endocrinol, Sao Paulo - Brazil

^[5] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 - USA

^[6] Univ Lausanne, Div Endocrinol Diabet & Metab, Lausanne - Switzerland

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 183, n. 6, p. 647-656, DEC 2020.
• Web of Science Citations: 0

Abstract

Objective: Genomic alterations in Hurthle cell carcinomas (HCC) include chromosomal losses, mitochondria! DNA mutations, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/beta-catenin pathways. This study aimed at characterizing the mutational profile of HCC. Methods: Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including, among others, the MAPK, PI3K-AKT-mTOR, Wnt/beta-catenin, and Notch pathways. HCC was widely invasive in 57.5%, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up, 10% of patients presented with persistent/ recurrent disease, but there were no cancer-related deaths. Results: Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/beta-catenin pathway was most frequently affected (30%), followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features. Conclusions: This series of HCC presents a wide range of mutations in the Wnt/beta-catenin, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/beta-catenin pathway, particularly mutations in APC and FAT1, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/p-catenin pathway plays a critical role in this distinct thyroid malignancy. (AU)

• FAPESP's process: 15/14819-7 - NEXT GENERATION SEQUENCING FOR DETECTION OF MUTATIONS IN THYROID HURTHLE CELL CARCINOMAS
• Grantee: Debora Lucia Seguro Danilovic
• Support Opportunities: Regular Research Grants