Refining neoplasm risk in DICER1-related tumor predisposition

DICER1-related tumor predisposition is an autosomal dominant disorder predisposing to a broad spectrum of malignant and benign neoplasms, caused by germline pathogenic variants (PVs) in the DICER1 gene. We aimed to characterize the clinical features of DICER1-related tumor predisposition in a national referral cohort and to estimate neoplasm risk.

This retrospective study was conducted in a cohort of 945 patients who underwent DICER1 genetic testing at Institut Curie, Paris, using Sanger sequencing from 2012 to 2014 and Next Generation Sequencing from 2015 to 2023.

Among 584 index cases evaluated for DICER1-related tumor predisposition, 91 (16%) carried a germline DICER1 PV and 31 (5%) harbored only somatic DICER1 PVs. Several tumors that were not previously part of the DICER1 tumor spectrum were identified. ETMR-like brain tumor and testicular Sertoli cell tumor are now recognized as DICER1-related neoplasms, and schwannoma is a strong candidate. The neoplasm risk was estimated in 170 relatives carrying a germline DICER1 PV. The cumulative incidence of malignant neoplasms was 4.8% [95% CI: 2.1% - 9.1%] at 10 years and 15.8% [95% CI: 8.9% - 24.7%] at 50 years. Overall neoplasm risk was significantly higher in females, primarily driven by the higher incidence of thyroid follicular nodular disease.

This large cohort study provides a comprehensive overview of the distribution of neoplasms associated with DICER1-related tumor predisposition. Broader genetic testing identified additional DICER1-related neoplasms, and schwannoma emerged as a candidate association. Finally, this study confirms the moderate penetrance of germline DICER1 PVs.