ETA2024 Oral Presentations Oral Session 6: Translational thyroid cancer research (7 abstracts)
Clinically relevant germline genetic variants and somatic fusions underlying paediatric thyroid cancer risk and aggressiveness
Carolina Pires 1 , Hugo Lainé 2 , Anna C. Ehlers 3 , Ana Saramago 1 , Margarida M. Moura 1 , Marta Pojo 1 , Rafael Cabrera 4 , Stefan Hamelmann 5 , Daniel Schrimpf 5 , Rune Matthiesen 6 , Valeriano Leite 7 , Jingtao Lilue 2 , Felix Sahm 5 , Tiago Nunes da Silva 8 , Thomas G. P. Grünewald 3 & Branca Cavaco 9
1Instituto Português de Oncologia de Lisboa Francisco Gentil, Unidade de Investigação Em Patobiologia Molecular, Lisboa, Portugal; 2Instituto Gulbenkian de Ciência, Bioinformatics Unit, Oeiras, Portugal; 3German Cancer Research Center (Dkfz), Division of Translational Pediatric Sarcoma Research, Heidelberg, Germany; 4Instituto Português de Oncologia de Lisboa Francisco Gentil, Serviço de Anatomia Patológica, Lisboa, Portugal; 5University Hospital Heidelberg, Department of Neuropathology, Heidelberg, Germany; 6Nova Medical School Research, Universidade Nova de Lisboa, Computational and Experimental Biology Group, Lisboa, Portugal; 7Servico de Endocrinologia, Instituto Português de Oncologia de Lisboa, Nova Medical School | Faculdade de Ciências Médicas, Lisboa Codex, Portugal; 8Instituto Português de Oncologia de Lisboa, Instituto Português de Oncologia de Lisboa Francisco Gentil, Endocrinology, Lisbon, Portugal; 9Instituto Portugues DE Oncologia DE Lisboa DE Francisco Gentil, Unidade DE Investigação Em Patobiologia Molecular, Lisboa, Portugal
Introduction: Paediatric thyroid cancer (TC) is characterised by higher aggressiveness and recurrence rates compared to adult TC. The risk stratification system for paediatric TC is simplified relative to that of adults. Paediatric tumours mostly harbour gene fusions, while adult TC frequently present oncogenic point mutations. Yet, 40-50% of genomic alterations driving tumourigenesis and conferring aggressiveness to radiation-unrelated paediatric papillary TC (PTC) remain unknown.
Objective: To clinically and molecularly characterise a series of radiation-unrelated paediatric PTC cases.
Methods: Twenty-one paediatric PTC cases followed in our institution were stratified into 3 risk groups, according to American Thyroid Association (ATA) guidelines for paediatric TC. Tumours from 15 high-, 2 intermediate- and 4 low-risk cases, as well as 6 normal thyroid tissues were studied through whole-exome and transcriptome sequencing, and DNA methylation arrays. Bioinformatics analyses were performed to identify candidate genetic variants, rearrangements, and methylation/expression patterns.
Results: Seven male and 14 female patients, aged 5-18 years, were studied. All patients remain alive as of the latest update, with high-risk cases often requiring ≥ 2 I131 treatments. In the transcriptome analysis, the high-risk group showed lower expression of thyroid differentiation-related genes and upregulation of MAPK signalling genes, compared to the other groups. Exome analysis unveiled genetic alterations in 17/21 (81%) patients, with 11 patients (52%) carrying germline variants classified in silico as likely pathogenic in known tumour predisposition genes [ CHEK2 (n = 1), DICER1 (n = 1)], thyroid function-related, and other genes [ HHEX (n = 1), FOXE1 (n = 2), DUOX1 (n = 1), DUOX2 (n = 1), AXIN1 (n = 1), FGFR4 (n = 1), NTHL1 (n = 1), ROS1 (n = 1)]. Additional variants are being evaluated. DICER1 variants (germline and somatic) were found exclusively in low-risk patients (4/4), all presenting two hits. Noteworthy, BRAF V600E and RAS hotspot mutations were absent in all cases. Gene fusions were identified in 43% of PTC [ RET (67%), NTRK (33%)], coexisting or not with the aforementioned germline variants. Global methylation analysis clearly grouped tumours into risk-related clusters.
Conclusions: The high prevalence of germline variants identified in this study suggests that hereditary predisposition frequently underlies TC aetiology in radiation-unrelated paediatric cases. Particularly, these results reinforce the role of DICER1 as driver of less aggressive paediatric PTC. The detection of somatic gene fusions, mainly in the high-risk cases, supports patients’ eligibility for available targeted therapies. Methylation profiling highlighted its potential utility for risk stratification and prognostic assessment. The ongoing study of an additional validation cohort of 18 paediatric cases may provide molecular support for current ATA guidelines.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more