Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Idoia Martínez de LaPiscina, Laura C Hernández-Ramírez, Nancy Portillo, Ana L Gómez-Gila, Inés Urrutia, Rosa Martínez-Salazar, Alejandro García-Castaño, Aníbal Aguayo, Itxaso Rica, Sonia Gaztambide, Fabio R Faucz, Margaret F Keil, Maya B Lodish, Martha Quezado, Nathan Pankratz, Prashant Chittiboina, John Lane, Denise M Kay, James L Mills, Luis Castaño, Constantine A Stratakis, Idoia Martínez de LaPiscina, Laura C Hernández-Ramírez, Nancy Portillo, Ana L Gómez-Gila, Inés Urrutia, Rosa Martínez-Salazar, Alejandro García-Castaño, Aníbal Aguayo, Itxaso Rica, Sonia Gaztambide, Fabio R Faucz, Margaret F Keil, Maya B Lodish, Martha Quezado, Nathan Pankratz, Prashant Chittiboina, John Lane, Denise M Kay, James L Mills, Luis Castaño, Constantine A Stratakis

Abstract

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. Clinical trial registration: ClinicalTrials.gov: NCT00001595.

Keywords: Cushing's disease; DICER1; corticotropinoma; disease-modifying gene; pituitary neuroendocrine tumor.

Copyright © 2020 Martínez de LaPiscina, Hernández-Ramírez, Portillo, Gómez-Gila, Urrutia, Martínez-Salazar, García-Castaño, Aguayo, Rica, Gaztambide, Faucz, Keil, Lodish, Quezado, Pankratz, Chittiboina, Lane, Kay, Mills, Castaño and Stratakis.

Figures

Figure 1
Figure 1
Representative preoperative MRI images of the PitNETs diagnosed in Cases 1–4, 6, and 7. Image for Case 5 was obtained after her first surgery (preoperative image not available). Blue arrows: tumors, yellow arrows: medial lobe cyst.
Figure 2
Figure 2
DICER1 protein comparison against different species and structure diagram of the protein. (A) Alignment of the DICER1 protein sequence across species. Position of the identified amino acid variants is presented in bold characters. Most of the identified variants are well conserved across species. (B) Scheme of the structure of the DICER1 protein and localization of studied variants. The main functional domains of DICER1 are the helicase domain including DEXD/H (DEAD box), TRBP-BD (trans-activation response RNA-binding protein-binding), HELICc (helicase conserved carboxy-terminal domain), and DUF283 (domain of unknown function), followed by a platform domain which separates the PAZ (Piwi/Argonaute, Zwille) domain from the two distinct RNase III domains (RNase IIIa and RNase IIIb) and the double-stranded RNA-binding domain (RBD). Localization of the DICER1 variants of interest described in this study is indicated by an arrow. Aa, amino acid.
Figure 3
Figure 3
Immunostaining for DICER1 in PitNETs and normal pituitary. Representative images are presented for Cases 1–6 (no slides were available for staining for Case 7), as well as for a corticotropinoma from a patient with no DICER1 variants of interest and for a normal pituitary specimen. Magnification for all images: 20 ×.

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