Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.
Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.
Department of Human Genetics, McGill University, 845 Rue Sherbrooke Ouest, Montreal, QC, H3A 0G4, Canada.
Leanne
L
de Kock
Nelly
N
Sabbaghian
François
F
Plourde
Archana
A
Srivastava
Evan
E
Weber
Dorothée
D
Bouron-Dal Soglio
Nancy
N
Hamel
Joon Hyuk
JH
Choi
Sung-Hye
SH
Park
Cheri L
CL
Deal
Megan M
MM
Kelsey
Megan K
MK
Dishop
Adam
A
Esbenshade
John F
JF
Kuttesch
Thomas S
TS
Jacques
Arie
A
Perry
Heinz
H
Leichter
Philippe
P
Maeder
Marie-Anne
MA
Brundler
Justin
J
Warner
James
J
Neal
Margaret
M
Zacharin
Márta
M
Korbonits
Trevor
T
Cole
Heidi
H
Traunecker
Thomas W
TW
McLean
Fabio
F
Rotondo
Pierre
P
Lepage
Steffen
S
Albrecht
Eva
E
Horvath
Kalman
K
Kovacs
John R
JR
Priest
William D
WD
Foulkes
D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008279:Magnetic Resonance Imaging; D009154:Mutation; D018193:Neoplasms, Complex and Mixed / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D013902:Radiography, Thoracic; D043244:Ribonuclease III / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases