Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.
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.
International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA. krisann.schultz@childrensmn.org.|International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA. krisann.schultz@childrensmn.org.|Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA. krisann.schultz@childrensmn.org.
Kris Ann P
KA
Schultz
International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA.|International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.|Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Anne
A
Harris
International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA.|International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.|Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Yoav
Y
Messinger
Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Susan
S
Sencer
Virginia Piper Cancer Institute, Allina Health, Minneapolis, MN, USA.
Shari
S
Baldinger
Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA.
Louis P
LP
Dehner
Division of Anatomic Pathology and Center for Genetic Medicine Research, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
D Ashley
DA
Hill
D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D012042:Registries; D043244:Ribonuclease III / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*
C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
DICER1; MiRNA; Ovarian cancer; Sarcoma; Sertoli-Leydig cell tumor