DICER1 Syndrome: DICER1 Mutations in Rare Cancers

Abstract

DICER1 syndrome is a rare genetic disorder that predisposes individuals to multiple cancer types. Through mutations of the gene encoding the endoribonuclease, Dicer, DICER1 syndrome disrupts the biogenesis and processing of miRNAs with subsequent disruption in control of gene expression. Since the first description of DICER1 syndrome, case reports have documented novel germline mutations of the DICER1 gene in patients with cancers as well as second site mutations that alter the function of the Dicer protein expressed. Here, we present a review of mutations in the DICER1 gene, the respective protein sequence changes, and clinical manifestations of DICER1 syndrome. Directions for future research are discussed.

Keywords: DICER1 germline mutations; DICER1 syndrome; cancer; miRNA; rare genetic disorder.

Figure 1

miRNA Production Pathway. DNA sequences are transcribed into RNA sequences that form a ‘hairpin’ structure of precursor miRNA. Drosha, a nucleic endoribonuclease, cleaves the hairpin from the primary RNA strand. Transported out of the nucleus by exportin 5, they are further processed by Dicer. After processing by Dicer and its accessory proteins, the hairpin structure of the precursor miRNA is degraded, leaving a single, linear piece of miRNA (the opposing piece is degraded by intracellular processes). This single piece is then bound by the RNA-induced silencing complex RISC. The RISC-miRNA complex binds to target mRNA strands, inhibiting translation by the ribosome.

Figure 2

DICER1 Pathogenic Germline Mutations. Mutations reported in DICER1 include deletions, duplications, insertions, transitions, or transversions. The DICER1 gene encodes 1922 amino acids, arranged into specific domains including the helicase 1/2, ATP-binding domain, the helicase, C-terminal domain, the Dicer dimerization domain (DDD), the PAZ domain (PAZ), the ribonuclease IIIa domain, and the ribonuclease IIIb domain. (see Tables 1–3).

Figure 3

The two-hit hypothesis. One germline mutation in a DICER1 allele predisposes the individual to an increased risk for benign and malignant tumors. A second somatic mutation in the other allele arising during tumorigenesis may lead to malignant rare cancers. While the first mutation by itself is overtly harmless, it only acts in tandem with the second to induce cancerous formation, according to the hypothesis.