Titolo progetto: PRIN2022 PNRR - An integrated analytical pipeline to overcome the missing heritability issue in familial non-medullary thyroid cancer.

Programma di finanziamento: PRIN 2022

Responsabile scientifico: dott.ssa Catia Mio

Ruolo del DAME: partner

Descrizione generale:

It is well known that patients affected by hereditary carcinomas possess germline alterations in either oncogenes or tumor-suppressor genes representing useful diagnostic tools and therapeutic targets in disease management. Indeed, a comprehensive and accurate family cancer history is essential for cancer risk assessment, reflecting complex interactions among inherited genetic susceptibilities, shared environmental and behavioral factors. Differentiated thyroid carcinomas of follicular origin (Non-Medullary Thyroid Carcinoma – NMTC) represent approximately 1.5% of all cancers and are the most widespread malignancy of the endocrine system, displaying a steadily increasing prevalence. When two or more first-degree relatives present thyroid cancer, it is classified as familial NMTC (FNMTC), which accounts for about 5-10% of all thyroid cancers. About 5% of FNMTC are part of syndromic forms with well-defined driver germline mutations (i.e., APC in Gardner syndrome and PTEN in Cowden syndrome); for the remaining, only low-penetrant susceptibility genes have been assessed. Many genome wide association studies (GWAS) have apparently shown good evidence for putative susceptibility genes, but subsequent investigation has contradicted these findings. Indeed, published studies (mostly based on whole exome sequencing – WES - of families) have failed to define high-risk predisposing gene variants and have shed more light on the “missing” heritability of FNMTC. The aim of this proposal is to set up a robust analytical pipeline developed by four interconnecting research units meant to identify a list of FNMTC-predisposing variants that could enable cancer susceptibility assessment within families and provide novel biomarkers and therapeutic targets. A cohort of 11 wellcharacterized families has already been enrolled. Patients’ DNA will be analyzed by whole genome SNPgenotyping and whole genome sequencing to identify familial segregation and candidate germline variants associated to FNMTC. Seeking a step forward from previously reported studies, we will assess the effects of the aforementioned variants using in vitro investigations. Gene-based down- or over-expression in thyroid cell lines will be performed to assess cancer-linked phenotypes. Additionally, CRISPR/Cas9 approaches will be used to further evaluate biological effects of candidate variants in thyroid cells. Undeniably, identification of novel candidate variants in FNMTC could both provide new molecular markers for the diagnosis of hereditable thyroid cancers and highlight new thyroid specific pathways altered during tumorigenesis, which could support genetic counseling and clinical management. Finally, the analytical pipeline outlined in this project could be used as model for the study of other genetic diseases, including non-oncological ones.

Partner del progetto:                                                                                

• Università degli studi di Roma “La Sapienza”
• Università degli studi di Udine 
• Università degli studi di Padova
• Università degli studi del Sannio di Benevento

Date inizio e fine progetto: 29.11.2023 – 28.11.2025

Budget totale del progetto: 65.085,00€

Sito web: https://prin.mur.gov.it/ 

Finanziato dall’Unione europea – Next Generation EU