Germline and somatic DICER1 mutations in a pituitary blastoma causing infantile-onset Cushing's disease.
BACKGROUND
Pituitary blastoma causing Cushing's syndrome in infancy is very rare, and its molecular pathomechanism is not well understood.


OBJECTIVE
Our objective was to identify genetic changes of a pituitary blastoma causing infantile-onset Cushing's syndrome in a Thai girl without a family history of cancers.


METHODS
Genomic DNA from both leukocytes and tumor tissues was used for whole-exome sequencing (WES) and Sanger sequencing of DICER1. The cDNA reverse-transcribed from RNA extracted from both leukocytes and tumor tissues was used for Sanger sequencing, quantitative real-time PCR (qRT-PCR), and pyrosequencing of DICER1.


RESULTS
WES of leukocytes identified a novel heterozygous c.3046delA (p.S1016VfsX1065) mutation in the DICER1 gene. WES of the tumor tissues detected the same frameshift germline mutation and another novel somatic missense c.5438A→T (p.E1813V) mutation. Both mutations were validated by Sanger sequencing. Quantitative real-time PCR revealed that the DICER1 mRNA levels of the tumor tissues were 54% compared with those of her leukocytes. Pyrosequencing showed that the deletion allele constituted 12% and 0% of the DICER1 cDNA of the proband's leukocytes and tumor tissues, respectively.


CONCLUSIONS
Our study extends the phenotypic and mutational spectrum of DICER1 mutations to include infantile-onset Cushing's disease and 2 novel mutations. Loss of function of both DICER1 alleles appears to be crucial to initiate tumor development.
Division of Pediatric Endocrinology (T.S., S.P.), Center of Excellence for Medical Genetics, Department of Pediatrics (C.S., S.K., K.S., V.S.), Division of Neurosurgery, Departments of Surgery (J.A.) and Pathology (S.S.), Faculty of Medicine, Chulalongkorn University; and Excellence Center for Medical Genetics (C.S., S.K., K.S., V.S.), King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand.
Taninee
T
Sahakitrungruang
Chalurmpon
C
Srichomthong
Sopon
S
Pornkunwilai
Jiraporn
J
Amornfa
Shanop
S
Shuangshoti
Supasak
S
Kulawonganunchai
Kanya
K
Suphapeetiporn
Vorasuk
V
Shotelersuk
D000367:Age Factors; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D009373:Neoplasms, Germ Cell and Embryonal / Q000150:complications / Q000235:genetics*; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000150:complications / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D013785:Thailand
C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases