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.
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Acknowledgments
The authors wish to thank the patients discussed in this manuscript and their families for their support of DICER1- related research. In addition we are grateful to the many patients, families, genetic counselors and treating physicians who participate in the International OTST Registry and to the Pine Tree Apple Tennis Classic, St. Baldrick’s Foundation, Randy Shaver Community Cancer Fund and Hyundai Hope on Wheels for their ongoing support of cancer research.
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This work is supported by National Institutes of Health grant NCI R01CA143167 (DAH,YM, KAS) and The Parson’s Foundation (DAH). The International Ovarian and Testicular Stromal Tumor Registry is supported by St. Baldrick’s Foundation, the Pine Tree Apple Tennis Classic, Hyundai Hope on Wheels and the Randy Shaver Community Cancer Fund.
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Schultz, K.A.P., Harris, A., Messinger, Y. et al. Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry. Familial Cancer 15, 105–110 (2016). https://doi.org/10.1007/s10689-015-9831-y
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DOI: https://doi.org/10.1007/s10689-015-9831-y