History of DICER1 mutation DICER1 function Mutated DICER1 – tumorigenic mechanism Constellation of lesions associated with DICER1 DICER1 IHC When to test? Therapeutic options

1. DICER1
MUTATIONS IN
TUMORS
M O D E R ATO R : P R O F U M A N A H A R S A I K I A

2. OUTLINE OF CLASS
• History of DICER1 mutation
• DICER1 function
• Mutated DICER1 – tumorigenic mechanism
• Constellation of lesions associated with DICER1
• DICER1 IHC
• When to test?
• Therapeutic options

3. ASSOCIATION AND
ORIGINS

6. Pleuropulmonary blastoma

7. Source : International Pleuropulmonary Blastoma/DICER1
registry

10. DISCOVERY OF DICER1

14. DICER 1
Chromosome 14q32.13 1922 amino acids 27 exons

15. HEAD:
Binding pockets
for 3’ and 5’ end
of dsRNA
BASE/ARM:
Reorganise into ‘L’ shape
and clamp the dsRNA
BODY:
Enzymes to splice the ds
RNA
RULER:
To
assign
length
Lau P et al. The Molecular Architecture of Human
Dicer. Nat Struct Mol Biol. 2012; 19(4): 436–440

17. EUREK A MOMENT !
CAUSE – EFFECT
REL ATIONSHIP

19. Oncogene
(gain of function of
genes)
Tumour suppressor
(loss of function of
genes)
Foulkes WD et al. DICER1: Mutations, microRNAs and
mechanisms. Nature Reviews Cancer. 2014

20. Kundson’s hypothesis
applies to DICER1
mutations
Autosomal dominant
(incomplete penetrance)
However, requires ‘Second’
hit in form of somatic
mutation in normal allele
Robertson JC et al. DICER1 Syndrome: DCER1 mutations
in rare cancers. Cancers. 2018; 10(5):143

21. Mutational landscape of DICER1 gene
Foulkes WD et al. DICER1: Mutations, microRNAs and
mechanisms. Nature Reviews Cancer. 2014

22. DICER1 ROLE IN
TUMOURS –
EXPONENTIAL RATE OF
DISCOVERIES

23. PLEUROPULMONARY BLASTOMA
• Most common primary malignant neoplasm of lung in children
• 3 types – I, II, III
• 75% have heterogyzous germline mutation in DICER1
• Remaining have somatic mutations in DICER1
• Third most common heritable solid malignancy after paraganglioma and
medullary carcinoma thyroid

24. • Type 1 ~ Congenital cystic
adenomatoid malformation IV
with stromal hypercellularity
• Potentially curable
• Multilocular mass
• Absence of intervening lung
parenchyma
• Cambium layer of immature
mesenchymal cells

25. • Type II & III
• Obvious malignant
stromal cells
• II – Solid cystic
• III – Solid
• Misdiagnosed as
Embryonal
rhabdomyosarcoma
Robertson JC et al. DICER1 Syndrome: DCER1 mutations
in rare cancers. Cancers. 2018; 10(5):143

26. PEDIATRIC CYSTIC NEPHROMA
• Children <5
• Multicystic renal neoplasm
• Characteristic ovarian like
stroma
• 90% have DICER1
mutation
• Can undergo sarcomatous
transformation
WHO Classification of tumors of the urinary system and
male genital organs, 4th edition, 2016

27. ANAPLASTIC SARCOMA OF KIDNEY
• Children, progress from cystic
nephroma
• All have DICER1 mutation
• Have in addition TP53 mutation
• Solid –cystic
• Undifferentiated spindle cells
with marked anaplastic changes
• Benign or malignant cartilage or
chondroid differentiation
• Less common: blastema-like
areas, foci of rhabdomyoblastic
differentiation, small islands of
osteoid
Wu MK et al. Anaplastic sarcomas of kidney are characterised by DICER1 mutations. Modern
pathology. 2018; 31: 169-178

28. SERTOLI-LEYDIG CELL TUMOR
• Moderately and Poorly differentiated SLCT of ovary
• Higher rates of recurrences with mesenchymal differentiation
• 80% show presence of DICER1 mutation
Stewart CJR eta l. Gynecologic manifestations of DICER1
syndrome. Surg Path Clinics. 2016; 9:227-241

29. NASAL CHONDROMESENCHYMAL
HAMARTOMA
• Intranasal/sinus polypoidal solid-
cystic mass in children
• Admixed of chondroid and
myxoid stroma
• ABC like areas
• Germline mutation seen in 75%
cases
Stewart DR et al. Nasal chrondromesenchymal
hamartomas. Hum Genet. 2014. 133;1443-50

30. CILIARY BODY MEDULLOEPITHELIOMA
• Ciliary body solid-cystic
mass in children
• Non-teratoid – proliferation
of primitive medullary
epithelium
• Teratoid - hyaline cartilage,
rhabdomyoblasts, striated
muscle, or brain-like tissue
Kaliki S et al. Ciliary body medulloepithelioma.
Ophthalmology.2013;120:2552-2559

31. THYROID- MUTLINODULAR GOITRE
• Multiple nodules in absence of
iodine deficiency
• Childhood and early adulthood
• Well differentiated neoplasm –
follicular and papillary carcinoma
• Additional RAS or BRAF mutations
• Indolent
• Prophylactic thyroidectomy not
warranted
Rutter MM et al. DICER1 mutations and differentiated
thyroid carcinoma. J Clin Endocrinol Metab.
2016:101:1-5

32. CERVICAL/BLADDER SARCOMA
BOTYROIDES
• Children and young adults
• Cluster of grapes
• Embryonal Rhabdomyosarcoma
• Nicholson Cambium layer
• >90% cases show DICER1
mutations
Doros L et al. DICER1 mutations in embryonal
rhabdomyosarcomas. Pediatr Blood Cancer.
2012:59:558-560

33. PINEOBLASTOMA
• Children and young adults
• Primitive cells in sheets and
occasional rosettes
• Risk of CSF seeding – metastases
• Most have Rb gene mutation
• However, 40% of cases may
harbour germline /somatic
mutation in DICER1
Kock L et al. An update on the CNS manifestations
of DICER1 syndrome. Acta Neuropathologica.2019.

34. PITUITARY BLASTOMA
• Children and young adults
• Rakthe like epithelial glands and
rosettes
• Primitive cells
• All have germline or somatic
DICER1 mutation
Kock L et al. An update on the CNS manifestations
of DICER1 syndrome. Acta Neuropathologica.2019.

35. EMBRYONAL TUMOR WITH MULTI-
LAYERED ROSETTES
• Infants
• Cerebellar location
• Germline mutation in DICER1
• Rhabdomyoblasts
Kock L et al. An update on the CNS
manifestations of DICER1 syndrome. Acta
Neuropathologica.2019.

36. PRIMARY CNS SARCOMA
• <5 years
• Leptomeningeal
• Hypercellular mesenchymal
tumor
• Rhabdomyoblasts
• Germline DICER1 mutation
Kock L et al. An update on the CNS
manifestations of DICER1 syndrome. Acta
Neuropathologica.2019.

37. OTHER LESIONS
Wilms tumor
Macrocephaly
Hamartomatous
polyp
Robertson JC et al. DICER1 Syndrome:
DCER1 mutations in rare cancers.
Cancers. 2018; 10(5):143

39. DICER1 – WHEN AND
HOW TO TEST ?

42. Indications for DICER1 testing
1 Major or 2 Minor

43. Blood, saliva or
fibroblast
For germline
mutation
Tumour tissue
For somatic mutation
Test for both germline and somatic mutation
when available

45. DICER1 IHC
• DICER1 antibody ab14601 (Abcam, Cambridge, MA, USA)
• anti-DICER1 antibody binds to a region within the PAZ domain of
the protein
Kock L et al. Germ-line and somatic DICER1 mutations in pineoblastoma.
Acta Neuropathol. 2014;128:583-595

46. SCREENING
STRATEGIES IN
PATIENTS WITH
GERMLINE MUTATIONS

47. Organ system Lesions Screening stragergy
Lung – PPB
– Lung cysts
– Pulmonary blastoma
CXR at birth and every 4–6
months until 8 years Every 12
months 8–12 years of age;
CT of chest at 3–6 months of
age
Thyroid – PPB
– Lung cysts
– Pulmonary blastoma
Baseline thyroid US by 8 years
Then every 3 years
Female reproductive tract – SLCT
– Gynandroblastoma
– Cervical ERMS
From 8 years - pelvic and
abdominal US every 6–12 mths
till 40
Renal – Wilms tumor
– Renal sarcoma
– Cystic nephroma
Abdominal US every 6 mths
until 8 yrs
Then every 12 mths
until 12 yrs
Gastrointestinal – Small intestine polyps Education regarding
recommended
Central nervous system – Macrocephaly
– Pineoblastoma
– Pituitary blastoma
– CBME
Annual ophthalmologic
exam from 3 yrs to 10 yrs
Urgent MRI for any symptoms
of intracranial pathology

48. THERAPEUTICS

51. SUMMARY
• DICER1 part of the process of assembly of RISC
• Mutation leads to tumour suppressor role
• Associated with a array of the tumours
• Histology: Primitive mesenchyme, embryonal cells, rhabdomyoblasts
• Predilection for multiple tumours in presence of germline mutations
• Testing for germline/somatic mutation
• Screening of children with germline mutations
• Therapeutic options ?

52. www.ppbregistry.or
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