DICER1 tumor predisposition syndrome is an autosomal dominant, pleiotropic tumor-predisposition disorder caused by germline pathogenic variants in DICER1, which encodes the RNase III endonuclease that generates mature microRNAs. Its tumor spectrum is unusually wide and developmentally timed — pleuropulmonary blastoma in infancy and early childhood, cystic nephroma, ovarian Sertoli-Leydig cell tumor, multinodular goitre and differentiated thyroid carcinoma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma and pineoblastoma — and the unifying lesion is not a growth-control pathway but the microRNA machinery itself. Two features set this syndrome apart from the classical two-hit tumor suppressor syndromes and both matter for curation. First, the somatic second event is not loss of function: germline alleles are typically truncating, while tumors characteristically acquire a missense change at a metal-binding residue of the RNase IIIb domain, selectively abolishing 5p-strand cleavage while leaving 3p-strand processing intact. The second hit therefore alters what the enzyme makes rather than abolishing the enzyme, which is why this entry does not conform to the biallelic-loss node of the two-hit module. Second, in pleuropulmonary blastoma the cell that loses DICER1 expression is the cyst epithelium while the cell that becomes malignant is the underlying mesenchyme, suggesting a non-cell-autonomous initiation in which loss of DICER1 in one compartment deranges diffusible signals that govern growth in another. Penetrance is only moderate: in systematically ascertained non-proband carriers, 5.3% had developed a neoplasm by age 10 and 19.3% by age 50, so most carriers of a DICER1 variant never develop a tumor.
Ask a research question about DICER1 Tumor Predisposition Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: DICER1 Tumor Predisposition Syndrome
creation_date: "2026-08-23T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Pediatric Cancer
parents:
- hereditary cancer-predisposing syndrome
disease_term:
preferred_term: DICER1-related tumor predisposition
term:
id: MONDO:0100216
label: DICER1-related tumor predisposition
synonyms:
- DICER1 syndrome
- pleuropulmonary blastoma familial tumor predisposition syndrome
- DICER1-related tumor predisposition syndrome
description: >-
DICER1 tumor predisposition syndrome is an autosomal dominant, pleiotropic
tumor-predisposition disorder caused by germline pathogenic variants in DICER1,
which encodes the RNase III endonuclease that generates mature microRNAs. Its
tumor spectrum is unusually wide and developmentally timed — pleuropulmonary
blastoma in infancy and early childhood, cystic nephroma, ovarian
Sertoli-Leydig cell tumor, multinodular goitre and differentiated thyroid
carcinoma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma and
pineoblastoma — and the unifying lesion is not a growth-control pathway but the
microRNA machinery itself.
Two features set this syndrome apart from the classical two-hit tumor
suppressor syndromes and both matter for curation. First, the somatic second
event is not loss of function: germline alleles are typically truncating,
while tumors characteristically acquire a missense change at a metal-binding
residue of the RNase IIIb domain, selectively abolishing 5p-strand cleavage
while leaving 3p-strand processing intact. The second hit therefore alters what
the enzyme makes rather than abolishing the enzyme, which is why this entry
does not conform to the biallelic-loss node of the two-hit module. Second, in
pleuropulmonary blastoma the cell that loses DICER1 expression is the cyst
epithelium while the cell that becomes malignant is the underlying mesenchyme,
suggesting a non-cell-autonomous initiation in which loss of DICER1 in one
compartment deranges diffusible signals that govern growth in another.
Penetrance is only moderate: in systematically ascertained non-proband
carriers, 5.3% had developed a neoplasm by age 10 and 19.3% by age 50, so most
carriers of a DICER1 variant never develop a tumor.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
expressivity: VARIABLE
description: >-
DICER1 syndrome is transmitted as an autosomal dominant predisposition with
incomplete, age- and sex-dependent penetrance. Most obligate carriers are
phenotypically normal, and after age 10 the risk in female carriers exceeds
that in males, driven largely by gynaecological and thyroid neoplasms.
evidence:
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition
disorder caused by pathogenic germline variants in DICER1.
explanation: >-
States the inheritance pattern and pleiotropy of the syndrome.
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After age 10 years, female risk was elevated compared with male risk.
explanation: >-
Supports the sex-dependence of penetrance asserted here, measured in
non-proband carriers to reduce ascertainment bias.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Each child of an individual with a germline constitutional DICER1
pathogenic variant has a 50% chance of inheriting the pathogenic variant.
explanation: >-
GeneReviews Genetic Counseling section: the transmission risk to
offspring. Evidence source is OTHER because GeneReviews is an
expert-authored review rather than a primary study.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Because the penetrance of heterozygous germline DICER1 pathogenic variants
is reduced, many individuals with a germline DICER1 pathogenic variant
remain clinically unaffected.
explanation: >-
GeneReviews Genetic Counseling section, and the direct basis for the
INCOMPLETE penetrance recorded here — consistent with the cumulative
incidence figures already curated, under which most carriers never develop
a neoplasm.
pathophysiology:
- name: Germline DICER1 First-Hit Inactivation
conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
description: >-
A heterozygous germline DICER1 variant is present constitutionally; in the
original multiplex pleuropulmonary blastoma families ten of eleven alleles
truncated the protein proximal to its two carboxy-terminal RNase III domains
and were therefore loss-of-function. Heterozygosity is well tolerated:
the majority of obligate carriers are phenotypically normal and mice
haploinsufficient for Dicer1 show no overt abnormality, so one functional
allele suffices for normal development and is insufficient for tumor
formation.
role: trigger
biological_scale: MOLECULAR
gene:
preferred_term: DICER1
modifier: DECREASED
term:
id: hgnc:17098
label: DICER1
genetic_context:
gene:
preferred_term: DICER1
term:
id: hgnc:17098
label: DICER1
variant_origin: GERMLINE
allelic_hit_role: FIRST_HIT
allelic_events:
- PATHOGENIC_VARIANT
- NONSENSE_VARIANT
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Constitutional heterozygous DICER1 variant, predominantly truncating
proximal to the RNase III domains.
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we show that 11 multiplex PPB families harbor heterozygous germline
mutations in DICER1, a gene encoding an endoribonuclease critical to the
generation of small noncoding regulatory RNAs.
explanation: >-
Identifies the germline first hit and the gene's function in the families
that defined the syndrome.
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apart from PPB-associated tumors in a subset of family members, the
majority of obligate carriers with DICER1 mutations are phenotypically
normal indicating that loss of one DICER1 allele is compatible with normal
development and insufficient for tumor formation.
explanation: >-
Directly supports the claim that the heterozygous constitutional state is
a susceptibility rather than a disease, which is what makes this a
first-hit node.
downstream:
- target: Compartment-Restricted Loss of DICER1 Expression
description: >-
Tumor development requires a further, tissue-restricted event that removes
DICER1 function from a specific cellular compartment.
- name: Compartment-Restricted Loss of DICER1 Expression
description: >-
In pleuropulmonary blastoma, DICER1 protein is undetectable in the epithelial
component of the tumor but retained in the malignant mesenchyme — the
opposite of what a conventional second-hit model would predict, since it is
the mesenchyme that transforms. This node deliberately does NOT declare
conformance to the biallelic-loss node of the germline two-hit module: the
somatic event characteristic of DICER1 tumors is a missense change in the
RNase IIIb domain that alters strand-selective processing rather than
abolishing the enzyme, and the compartment in which expression is lost is not
the compartment that becomes malignant.
role: amplifier
biological_scale: CELLULAR
biological_processes:
- preferred_term: pre-miRNA processing
term:
id: GO:0031054
label: pre-miRNA processing
modifier: DECREASED
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Expression of DICER1 protein was undetectable in the epithelial component
of PPB tumors but was retained in the malignant mesenchyme (sarcoma).
explanation: >-
The immunohistochemical observation that establishes the compartment
restriction and is the reason this entry withholds conformance to the
classical biallelic node.
downstream:
- target: Non-Cell-Autonomous Mesenchymal Transformation
description: >-
Loss of DICER1 in the epithelium is proposed to derange diffusible signals
that govern growth of the adjacent mesenchyme.
- name: Non-Cell-Autonomous Mesenchymal Transformation
description: >-
The proposed mechanism linking epithelial DICER1 loss to mesenchymal
malignancy: without normal microRNA processing, the developing lung
epithelium mis-regulates diffusible factors that control proliferation of the
mesenchymal cells in the cyst wall, which then expand and acquire further
genetic changes. This is explicitly a hypothesis in the source and is curated
as such rather than as established mechanism; the cystic-to-sarcomatous
natural history of pleuropulmonary blastoma is itself the observation that
suggests a multi-step pathogenesis.
role: effector
biological_scale: TISSUE
biological_processes:
- preferred_term: cell population proliferation
term:
id: GO:0008283
label: cell population proliferation
modifier: INCREASED
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We hypothesize that loss of DICER1 in the epithelium of the developing
lung alters the regulation of diffusible factors that promote mesenchymal
proliferation.
explanation: >-
The authors' own statement of the non-cell-autonomous hypothesis. The
hedged wording is preserved here: this is a proposal, not a demonstrated
mechanism.
downstream:
- target: Pleiotropic Childhood-Onset Neoplasm Spectrum
description: >-
The equivalent process in other developing organs produces the syndrome's
characteristic multi-organ tumor spectrum.
- name: Pleiotropic Childhood-Onset Neoplasm Spectrum
conforms_to: "germline_two_hit_tumor_predisposition#Early-Onset, Multifocal, and Bilateral Tumor Spectrum"
description: >-
The clinical output: a wide but characteristic set of neoplasms whose timing
follows the development of the affected organ — pleuropulmonary blastoma and
cystic nephroma in early childhood, ovarian Sertoli-Leydig cell tumor and
thyroid disease later. Quantified in systematically ascertained non-proband
carriers, cumulative neoplasm incidence is 5.3% by age 10 and 19.3% by age
50, with significant excess of gynaecological and thyroid cancers relative to
population rates.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had
developed a neoplasm (females, 26.5%; males, 10.2%).
explanation: >-
Quantifies cumulative neoplasm incidence in carriers ascertained so as to
minimise bias, which is the risk figure this consequence node asserts.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The majority of tumors occur in individuals younger than age 40 years. PPB
typically presents in infants and children younger than age seven years.
explanation: >-
GeneReviews Clinical Characteristics section, giving the developmental
timing this consequence node asserts — tumors track the development of the
affected organ rather than accumulating with age as in the adult-onset
predisposition syndromes.
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Standardized cancer incidence ratio analysis of 102 nonproband DICER1
carriers, which represented 3,344 person-years of observation, showed
significant cancer excesses overall, particularly of gynecologic and
thyroid cancers.
explanation: >-
Establishes the excess malignancy risk and identifies the organ systems
that dominate it.
phenotypes:
- category: Respiratory
name: Pleuropulmonary Blastoma
description: >-
The index tumor of the syndrome; a rare pediatric lung tumor progressing from
a purely cystic lesion to sarcomatous overgrowth, whose stage at presentation
determines outcome.
phenotype_term:
preferred_term: Pleuropulmonary blastoma
term:
id: HP:0100528
label: Pleuropulmonary blastoma
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pleuropulmonary blastoma (PPB) is a rare pediatric lung tumor that is
often part of an inherited cancer syndrome.
explanation: >-
Establishes pleuropulmonary blastoma as the defining tumor associated with
an inherited syndrome.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
PPB typically presents in infants and children younger than age seven
years.
explanation: >-
GeneReviews Clinical Characteristics section, giving the narrow age window
in which pleuropulmonary blastoma presents — the reason chest imaging
surveillance is front-loaded into early childhood.
- category: Renal
name: Cystic Nephroma
description: >-
Benign multicystic renal tumor of childhood, one of the two most frequent
additional neoplasms in families of children with pleuropulmonary blastoma.
phenotype_term:
preferred_term: Cystic nephroma
term:
id: HP:0034836
label: Cystic nephroma
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Approximately 20% of children with PPB have a family history of pediatric
neoplasia, most notably cystic nephroma of the kidney and
rhabdomyosarcoma.
explanation: >-
Identifies cystic nephroma as a characteristic familial co-occurring tumor
and quantifies how often a family history is present.
- category: Musculoskeletal
name: Rhabdomyosarcoma
description: >-
Embryonal rhabdomyosarcoma, notably of the cervix and other genitourinary
sites, is part of the DICER1 spectrum.
phenotype_term:
preferred_term: Rhabdomyosarcoma
term:
id: HP:0002859
label: Rhabdomyosarcoma
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Approximately 20% of children with PPB have a family history of pediatric
neoplasia, most notably cystic nephroma of the kidney and
rhabdomyosarcoma.
explanation: >-
Names rhabdomyosarcoma among the characteristic familial neoplasms.
- category: Endocrine
name: Multinodular Goiter
description: >-
Early-onset multinodular thyroid disease, frequent in carriers and one of the
two organ systems driving the excess cancer risk in adulthood.
phenotype_term:
preferred_term: Multinodular goiter
term:
id: HP:0005987
label: Multinodular goiter
evidence:
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The most common features are lung cysts and thyroid nodules.
explanation: >-
GeneReviews Clinical Characteristics section, naming thyroid nodules as
one of the two commonest features of the syndrome. This replaces the
placeholder note left when the available cohort study quantified thyroid
cancer rather than benign nodular disease.
- category: Endocrine
name: Thyroid Carcinoma
description: >-
Differentiated thyroid carcinoma; thyroid cancer is one of the two organ
systems that dominate the excess malignancy risk in DICER1 carriers.
phenotype_term:
preferred_term: Thyroid carcinoma
term:
id: HP:0002890
label: Thyroid carcinoma
evidence:
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Standardized cancer incidence ratio analysis of 102 nonproband DICER1
carriers, which represented 3,344 person-years of observation, showed
significant cancer excesses overall, particularly of gynecologic and
thyroid cancers.
explanation: >-
Establishes a significant excess of thyroid cancer specifically, measured
against SEER in non-proband carriers to limit ascertainment bias.
- category: Reproductive
name: Ovarian Neoplasm
description: >-
Ovarian sex cord-stromal tumors, characteristically Sertoli-Leydig cell
tumor, which may present with virilization.
phenotype_term:
preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: PMID:30715996
reference_title: Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Standardized cancer incidence ratio analysis of 102 nonproband DICER1
carriers, which represented 3,344 person-years of observation, showed
significant cancer excesses overall, particularly of gynecologic and
thyroid cancers.
explanation: >-
Names gynaecologic cancer as a dominant component of the carrier excess,
which is the claim this phenotype makes. The sex-difference sentence used
previously here described penetrance, not the ovarian phenotype, and is
cited on the inheritance block where it belongs.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Ovarian sex cord-stromal tumors are most often diagnosed before age 40
years.
explanation: >-
GeneReviews Clinical Characteristics section, identifying the ovarian
tumor class (sex cord-stromal, of which Sertoli-Leydig cell tumor is the
characteristic type) and its age distribution.
genetic:
- name: DICER1
gene_term:
preferred_term: DICER1
term:
id: hgnc:17098
label: DICER1
relationship_type: CAUSATIVE
notes: >-
DICER1 at 14q32 encodes an RNase III endonuclease that generates mature
microRNAs. Germline truncating variants cause the syndrome; tumors
characteristically acquire a somatic RNase IIIb missense change rather than a
second loss-of-function allele.
evidence:
- reference: PMID:19556464
reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 encodes a ~218 kDa RNase III endonuclease that is a key component
of a highly conserved cellular pathway responsible for generation of small
RNAs (miRNAs and siRNAs).
explanation: >-
Identifies the gene product and its molecular function.
treatments:
- name: Age-Structured Tumor Surveillance
notes: >-
Curated under `treatments:` as a management intervention, not as a claim
that imaging or biochemistry is itself therapeutic. In a two-hit
predisposition syndrome the second hit cannot be prevented, so the only
available lever is stage at detection: surveillance is the intervention
that converts an unavoidable tumor into a resectable one. Where a
`target_mechanisms` link is present it points at the clinical-outcome node
for that reason, and never at an upstream mechanistic node.
description: >-
Surveillance in DICER1 syndrome is structured around organ development
rather than run at a constant rate: chest imaging is dense in infancy and
early childhood when pleuropulmonary blastoma presents, then tapers; thyroid
ultrasound starts at age eight; pelvic ultrasound covers the gynaecological
tumors of adolescence and early adulthood. GeneReviews puts family education
about symptoms first, ahead of any imaging schedule.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: Ultrasound Imaging
term:
id: NCIT:C17230
label: Ultrasound Imaging
target_mechanisms:
- target: Pleiotropic Childhood-Onset Neoplasm Spectrum
treatment_effect: INHIBITS
description: >-
Surveillance shifts detection earlier within the developmental window in
which each tumor arises; it does not alter the germline variant or the
compartment-restricted events downstream of it.
evidence:
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Family education regarding signs and symptoms of DICER1-related tumors is
the cornerstone of surveillance.
explanation: >-
GeneReviews Management section. Education is placed ahead of imaging
because the tumor spectrum is too broad and too age-dispersed for any
single imaging protocol to cover.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
chest radiograph at birth, every six months until age eight years, then
annually until age 12 years. Chest CT at age three months and age 30
months.
explanation: >-
GeneReviews Management section, giving the front-loaded chest surveillance
schedule that matches the infancy-to-early-childhood presentation of
pleuropulmonary blastoma.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Thyroid ultrasounds every three years beginning at age eight years.
explanation: >-
GeneReviews Management section, giving the thyroid surveillance interval
and start age for the syndrome's commonest endocrine feature.
- name: Tumor-Directed Surgery and Chemotherapy
description: >-
There is no DICER1-specific therapy; treatment is by tumor type and stage,
most often surgical resection with or without chemotherapy. Radiation is
used more selectively — for residual or recurrent type II/III
pleuropulmonary blastoma and for the CNS tumors — which matters in a
syndrome where a carrier may face several primaries over a lifetime.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Surgical Procedure
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Pleiotropic Childhood-Onset Neoplasm Spectrum
treatment_effect: INHIBITS
description: >-
Treats the established tumor; the constitutional variant and the risk of
further independent tumors are unchanged, which is why surveillance
continues after successful treatment.
evidence:
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Treatment for DICER1-associated malignant tumors is dependent on tumor
type and stage. Most often, treatment involves surgical resection with or
without chemotherapy.
explanation: >-
GeneReviews Management section, stating the general treatment approach
across the tumor spectrum.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The treatment of type II or III PPB and certain other malignant tumors may
also include radiation, primarily to treat residual disease or recurrence.
explanation: >-
GeneReviews Management section, giving the restricted indication for
radiotherapy.
diagnosis:
- name: Molecular Genetic Testing for Germline DICER1 Loss of Function
description: >-
The diagnosis rests on a heterozygous germline DICER1 variant known or
suspected to cause loss of function. The zygosity and the mechanism in that
sentence both matter for this entry: the constitutional variant is
loss-of-function and heterozygous, whereas the somatic event characteristic
of DICER1 tumors is an RNase IIIb missense change that alters rather than
abolishes enzyme activity — which is why this entry conforms only partially
to the two-hit module.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
results: >-
A heterozygous germline loss-of-function DICER1 variant establishes the
diagnosis and starts age-structured surveillance.
evidence:
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The diagnosis of DICER1 is established by identification of a heterozygous
germline DICER1 pathogenic variant that is known or suspected to cause
loss of function.
explanation: >-
GeneReviews Diagnosis/Testing section, stating the confirmatory test and
specifying loss of function — the germline mechanism, distinct from the
somatic hotspot missense change found in the tumors.
- name: Fine-Needle Aspiration of Concerning Thyroid Nodules
description: >-
Because thyroid nodules are among the commonest features and most are
benign, the diagnostic question is which to sample. GeneReviews directs this
by age-appropriate general guidelines rather than a DICER1-specific rule,
with an added indication after chemotherapy exposure.
diagnosis_term:
preferred_term: Fine-Needle Aspiration
term:
id: NCIT:C15361
label: Fine-Needle Aspiration
results: >-
Distinguishes the common benign nodule from differentiated thyroid carcinoma
within the DICER1 tumor spectrum.
evidence:
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Thyroid nodules that have concerning features may require biopsy
(generally fine-needle aspiration [FNA]) and/or surgical resection.
explanation: >-
GeneReviews Management section, giving the indication for sampling a
thyroid nodule in a carrier.
- reference: PMID:24761742
reference_title: "DICER1-Related Tumor Predisposition."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Consider annual thyroid ultrasound for five years following the completion
of chemotherapy for individuals who have received chemotherapy.
explanation: >-
GeneReviews Management section, giving the intensified thyroid
surveillance that follows chemotherapy exposure in a carrier.
discussions:
- discussion_id: gap_dicer1_non_classical_second_hit
prompt: >-
Does DICER1-driven tumorigenesis require a classical second hit at the
DICER1 locus, and in which cellular compartment must that event occur?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Compartment-Restricted Loss of DICER1 Expression
- pathophysiology#Non-Cell-Autonomous Mesenchymal Transformation
rationale: >-
DICER1 does not fit the Knudson template cleanly, and pretending it does
would be a curation error rather than a simplification. The germline allele
is loss-of-function but the characteristic somatic event alters
strand-selective processing rather than abolishing the enzyme, so the tumor
cell is not DICER1-null. In pleuropulmonary blastoma the compartment lacking
DICER1 protein is the epithelium while the malignant compartment is the
mesenchyme, and the original report states plainly that the genetic basis of
the altered epithelial expression was unknown and that whether DICER1
haploinsufficiency in the mesenchyme contributes remains open. This entry
therefore conforms to the first-hit and tumor-spectrum nodes of the germline
two-hit module but deliberately not to its biallelic-loss node.
proposed_experiments:
- experiment_id: compartment_resolved_dicer1_genotyping_in_ppb
name: Compartment-resolved DICER1 genotyping and microRNA profiling in pleuropulmonary blastoma
description: >-
Separately genotype and microRNA-profile the epithelial and mesenchymal
compartments of the same pleuropulmonary blastoma specimens, to establish
which compartment carries which DICER1 allele, whether 5p-strand depletion
is confined to one of them, and whether the diffusible-factor hypothesis
predicts the observed mesenchymal transcriptome.
references:
- reference: PMID:24761742
title: "DICER1-Related Tumor Predisposition."
tags:
- GeneReviews
clinical_trials:
- name: NCT01247597
phase: NOT_APPLICABLE
status: RECRUITING
description: >-
Ongoing NCI natural history study of DICER1-related pleuropulmonary
blastoma and its associated tumor spectrum, the cohort from which most
DICER1 penetrance and surveillance data derive.
target_phenotypes:
- preferred_term: Pleuropulmonary blastoma
term:
id: HP:0100528
label: Pleuropulmonary blastoma
- preferred_term: Cystic nephroma
term:
id: HP:0034836
label: Cystic nephroma
evidence:
- reference: clinicaltrials:NCT01247597
reference_title: "DICER1-Related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To study individuals with a personal or a family history of pleuropulmonary blastoma (PPB) or other rare tumors that can be associated with PPB (e.g., cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, ocular medulloepithelioma).
explanation: >-
Registry record enumerating the DICER1 tumor spectrum this entry curates,
and establishing the prospective cohort behind it.