Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry

Abstract

Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.

Keywords: DICER1; MiRNA; Ovarian cancer; Sarcoma; Sertoli-Leydig cell tumor.

Fig. 1

Pathologic features of the primary ovarian sarcoma in Patient #1 with DICER1 mutation a. Low power view shows epithelial lined cysts, solid sarcoma and focal necrosis. b. Higher power view shows spindled and stellate cells in a pale mucoid matrix. c,d. Higher power views highlight areas with significant nuclear pleomorphism. (Hematoxylin and eosin; x100 (a), x200 (b,c,d)).

Fig. 2

Sertoli-Leydig cell tumor in the contralateral ovary of Patient #1. a. Low power view showing Leydig cells with abundant pink cytoplasm in upper left adjacent to nests of small Sertoli cells. b. Elongated tubules of Sertoli cells. c. Spindle cell pattern seen focally. d. Ribbons of Sertoli cells with hyperchromatic nuclei. (Hematoxylin and eosin; x100 (a), x400 (b,c,d))

Fig. 3. Pathologic features of the Sertoli-Leydig tumor in patient #2

a.Tubular structures and nests of Sertoli cells. b. Epithelial lined cyst with nest of Sertoli cells and rare anaplastic cells. c. Cystic structure within the SLCT. d. Focal mucinous gland. (Hematoxylin and eosin; x200 (a,b), x100 (c,d)).

Fig. 4. Unique intronic mutation in DICER1 resulting in duplication of splice site

a. Germline DICER1 sequencing results from Patient #1 (Lanes 5 and 6) compared with reference genome (Lanes 1–4). Intron-exon boundary indicated by vertical blue line with six base pairs of the splice site in the blue box. Mutated base NM_177438.2:c.5096-12 G>A in blue highlight. Putative new intron-exon boundary indicated by vertical red line. b. Sanger sequence chromatogram from Patient 1. Red arrow indicates heterozygous mutation site. c. Next generation sequence data as displayed with Integrative Genome Viewer [27, 28]. Red arrow highlights the mutated base.