Multiple DICER1‐related tumors in a child with a large interstitial 14q32 deletion

Abstract

Germ-line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer-predisposition gene located at 14q32.13. We report the case of a male child with a ∼5.8 Mbp 14q32.13q32.2 germ-line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome-related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle-cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein-coding genes. In addition to the germ-line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly-defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1-related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1-related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted.

Molecular Cytogenomic Characterization of the Murine Breast Cancer Cell Lines C-127I, EMT6/P and TA3 Hauschka

“…Moreover, in TA3 Hauschka and C-127I, breakpoints homologous to human band 14q32 could be observed. Notably, there, the gene DICER1 is located, recently identified as playing a role in cancer predisposition [ 30 , 32 ].…”

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

“…While most individuals with DICER1 syndrome are heterozygous for a germline loss‐of‐function DICER1 pathogenic variant, other predisposing DICER1 alterations have also been documented. These include deletion of the entire DICER1 locus (de Kock, Geoffrion, et al, ; de Kock et al, ; Herriges et al, ; van Engelen et al, ), in‐ and out‐of‐frame intragenic deletions involving one or more exons (Apellaniz‐Ruiz et al, ; Brenneman et al, ; Sabbaghian et al, ), and somatic mosaicism, which is observed in a small fraction of syndromic patients (Brenneman et al, ; de Kock et al, ; Klein et al, ). Individuals with mosaicism for loss‐of‐function mutations tend to exhibit one or two foci of disease; in contrast, mosaicism for RNase IIIb hotspot mutations results in a greater number of disease foci at significantly younger ages than is typical (Brenneman et al, ; de Kock et al, ).…”

A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1

“…In patients with Beckwith-Wiedemann syndrome and CDKN1C mutations, an extended phenotype including ear pits and polydactyly has been described. To date, ID/developmental delay has been reported in at least nine patients with large deletions encompassing several genes including DICER1, [21][22][23][24][25][26][27] and in three patients with RNase IIIb or RNase IIIa-S1344L hotspot mutations. 5 10 The highly penetrant and severe phenotypes described in patients with germline or mosaic RNase III domain mutations 5 6 may be explained by the likelihood of a second somatic mutation stochastically occurring in any part of DICER1 being greater than the reverse succession normally seen in DICER1 syndrome, in combination with tissue-specific neomorphic effects of the specific heterozygous RNase III domain mutations.…”