DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome.
BACKGROUND
Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB).


OBJECTIVE
To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer.


RESULTS
The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations.


CONCLUSIONS
Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.
Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, , 15 Cotswold Road, Sutton SM2 5NG, UK.
Ingrid
I
Slade
Chiara
C
Bacchelli
Helen
H
Davies
Anne
A
Murray
Fatemeh
F
Abbaszadeh
Sandra
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Hanks
Rita
R
Barfoot
Amos
A
Burke
Julia
J
Chisholm
Martin
M
Hewitt
Helen
H
Jenkinson
Derek
D
King
Bruce
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Morland
Barry
B
Pizer
Katrina
K
Prescott
Anand
A
Saggar
Lucy
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Side
Heidi
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Traunecker
Sucheta
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Vaidya
Paul
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Ward
P Andrew
PA
Futreal
Gordan
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Vujanic
Andrew G
AG
Nicholson
Neil
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Sebire
Clare
C
Turnbull
John R
JR
Priest
Kathryn
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Pritchard-Jones
Richard
R
Houlston
Charles
C
Stiller
Michael R
MR
Stratton
Jenny
J
Douglas
Nazneen
N
Rahman
D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases