ESPE Abstracts (2016) 86 P-P1-689

Novel Germline Mutations in DICER1 Gene in Patients with Different Pediatric Hereditary Tumors

Roxana Marino, Jesica Galeano, Pablo Ramirez, Natalia Perez Garrido, Elisa Vaiani, Mariana Costanzo, Viviana Herzovich, Noelia Dujovne, Fabiana Lubieniecki, Laura De la Rosa, Gabriela Obregón, Guillermo Chantada, Marco Rivarola Aurelio & Alicia Belgorosky


Hospital de Pediatría Garrahan, Buenos Aires, Argentina


Background: Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome, associated with tumors such as pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumors (SLCT), multinodular goiter (MNG), cystic nephroma (CN), embryonal rhabdomyosarcoma (ERMS) or primitive neuroectodermic tumor. DICER1 is involved in the generation of microRNAs (miRNAs), short, double-stranded, non-coding RNAs that modulate gene expression at the posttranscriptional level. Germline mutations in DICER1 would cause an alteration in miRNAs processing deregulating target oncogenes and leading to elevated risk of tumorigenesis. In most reported cases, there is an heterozygous germline mutation detected and a somatic second hit mutation in the wild type allele.

Objective and hypotheses: To analyze the presence of DICER1 germline gene alterations in four patients with pediatric tumors associated.

Method: Automated sequencing of DICER1 gene from gDNA extracted from blood of affected subjects and relatives. Clinical Cases: three girls (P1, P2, P4) and one boy (P3), chronological age at diagnosis were: 5, 12, 15, and 2 years, respectively. Pathological studies revealed in P1: bilateral ovarian SLCT, P2: ovarian SLCT and MNG P3: CN and P4; ovarian SLCT and MNG.

Results: P1, P2 and P3 were found to be heterozygous for the novel p.Trp1098*, p.Phe351fs*1 and p.Asp244Glyfs*27 variations respectively while P4 was found to be heterozygous for the previously described p.D1437Mfs*16 mutation. In P2 and P3 familial molecular studies the same alteration in one parent (father and mother respectively) was detected. It is predicted that these alterations would lead to a truncated protein above the RNAsa IIIa and RNAsa IIIb domains that includes metal-binding sites, and therefore without catalytic enzyme activity if translated.

Conclusion: We report three novel heterozygous frameshift mutations in the DICER1 gene. Molecular analysis of DICER1 gene allows identification of high-risk families, to perfom an early diagnosis and to offer a genetic counselling about familial recurrence risk.