Mutations and Epigenetic Defects

Question 1

GATA1

Answer 1

• Down Syndrome-related AMKL and TAM: Found in almost all patients with mutation almost always in Exon 2
• Arises in the fetal liver –> both AMKL and TAM
• Second hit mutation required to progress from TAM to AMKL

Question 2

NF1
NRAS
KRAS
PTPN11
CBL

Answer 2

• JMML: Found in 90%
• Activating germline or somatic mutations in the RAS pathway
• Possible spontaneous resolution with Noonan’s syndrome (germline PTPN11)

Question 3

BRAFV600E

Answer 3

• LCH: Found in 60%
• Some pilocytic astrocytomas: Found in 15% (most have BRAF-KIAA1549 fusion)
• Pleomorphic Xanthoastrocytoma: Found in 60%
• Melanoma: Found in 45%
• Papillary thyroid carcinoma (other adult cancers)

Question 4

H3K27M
mutation

Answer 4

• DIPG: Found in 80%
• Other midline gliomas

Question 5

MYCN

Answer 5

• Neuroblastoma: Found in 20%, most common amplification
• High-risk feature

Question 6

SMARCB1

Answer 6

• Rhabdoid tumors (including ATRT): Loss of SMARCB1 (aka INI1)
• Schwannomatosis

Question 7

WT1

Answer 7

• Sporadic Wilms tumor
• WAGR: Wilms tumor, aniridia, genitourinary malformations, developmental delay
• Denys-Drash syndrome

Question 8

FAS
FASL
CASP10

Answer 8

* ALPS: Diagnosis requires >6 months lymphadenopathy or splenomegaly with
increased** double-negative T cells**, and one primary accessory criterion (defective
lymphocyte apoptosis or characteristic mutation)
* Probable ALPS: No primary but one secondary accessory criterion
(1. Elevated plasma FASL, or IL-10, or IL-18, or vitamin B12 levels;
2. Consistent immunohistology;
3. Autoimmune cytopenias AND elevated IgG;
4. Family history of lymphoproliferation)

Question 9

gp47phox

Answer 9

• CGD: Found in 25%, autosomal recessive
• gp22phox and gp67phox each account for 5%
• Defects in NADPH oxidase

Question 10

gp91phox

Answer 10

• CGD: Found in 70%, X-linked
• Defects in NADPH oxidase

Question 11

PRF1
UNC13D
STX11
RAB27A
SH2D1A
XIAP, etc.

Answer 11

• Familial HLH: Most common mutations affect the perforin pathway (PRF1, UNC13D, STX11, STXBP2)
• Elevated risk of HLH: Griscelli syndrome (RAB27A), Hermansky-Pudlack (AP3B1), XLPS (SH2D1A or XIAP), XMEN syndrome (MAGT1)

Question 12

PIGA

Answer 12

• PNH: Somatic mutations lead to the deficiency of CD55/59
• Lack of CD55/59 on RBCs allows complement (C3) to activate the alternative pathway and mediate hemolysis
• Elevated risk of thrombosis (mechanism unclear)

Question 13

T315I

Answer 13

• BCR-ABL CML: Mutation conferring TKI resistance in CML patients
• Sensitive to Ponatinib (a 3rd generation TKI)

Question 14

11q-

Answer 14

• Neuroblastoma: Associated with TERT rearrangement and ATRX mutations
• Present in 30 to 40% of patients

Question 15

ALK

Answer 15

• Sporadic and familial neuroblastoma: Activating mutations or amplification
• ALCL: Translocation t(2;5)
• Inflammatory myofibroblastic tumor: 50% with ALK rearrangements

Question 16

ATRX

Answer 16

• Neuroblastoma: In-frame deletions in ATRX
• Patients typically present at an older age and a have a protracted course

Question 17

CTNNB1

Answer 17

• Hepatoblastoma: 90% of cases
• Hepatocellular carcinoma: 17-40% of cases
• Desmoid tumor: 85% of cases
• WNT subtype of medulloblastoma: 10% of cases

Question 18

**LOH 16q

Answer 18

• Wilms tumor
• Marker of worse outcome

Question 19

LOH 1p

Answer 19

• Wilms tumor: Marker of worse outcome
• Neuroblastoma: Associated with MYCN amplification, found in 30%

Question 20

PHOX2B

Answer 20

• Neuroblastoma: Loss-of-function germline mutations
• Associated with Hirschsprung disease and central hypoventilation

Question 21

TERT

Answer 21

• Neuroblastoma: Activating rearrangements in 13% of patients
• Dyskeratosis congenita: Telomeropathy

Question 22

ELA2 (ELANE)

Answer 22

• Severe congenital neutropenia: Autosomal dominant mutations, apoptosis of myeloid precursors with maturational arrest
• Cyclic neutropenia: Recurrent neutropenia (typically 21±4-day cycles)

Question 23

HAX1

Answer 23

• Kostmann syndrome: Subtype of severe congenital neutropenia
• Associated with neurological dysfunction

Question 24

Mitochondrial DNA Mutation

Answer 24

• Pearson syndrome: Bone marrow failure syndrome
• Associated with either neutropenia or anemia and pancreatic insufficiency
• Vacuolization of erythroid and myeloid precursors and ring sideroblasts in the bone marrow

Question 25

MPL

Answer 25

CAMT

Question 26

SBDS

Answer 26

Schwachman-Diamond syndrome

Question 27

13q-

Answer 27

• 13q deletion syndrome: Associated with severe developmental delay, multiple birth defects, and predisposition to retinoblastoma (RB is located on 13q)

Question 28

APC

Answer 28

• Familial adenomatous polyposis (FAP)
• Gardner subtype: Desmoid tumors, congenital hypertrophy of retinal pigment epithelium, osteomas
• Turcot subtype: Medulloblastoma

Question 29

BLM (aka. RECQL3)

Answer 29

• Bloom syndrome: Rare cancer predisposition syndrome (all types of cancers)
• Associated with very short stature and dermal sun sensitivity
• Loss-of-function of BLM causes chromosome instability and a significantly increased number of sister chromatid exchanges

Question 30

FANCB

Answer 30

• X-linked Fanconi anemia: Numerous different FANC genes cause Fanconi anemia, but FANCB is the only X-linked gene

Question 31

GPC3

Answer 31

• Simpson-Golabi-Behmel syndrome: Characterized by macrosomia, macrocephaly, macroglossia, intellectual disability, and variably other congenital disabilities
• Increased risk for Wilms tumor, hepatoblastoma, neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma

Question 32

PIK3CA

Answer 32

• CLOVES syndrome: Causes
  1. Congenital lipomatous overgrowth
  2. Vascular malformations
  3. Epidermal nevi
  4. Spinal abnormalities
• Overgrowth syndrome with risk of Wilms tumor (but not hepatoblastoma)

Question 33

SDHA
SDHB
SDHC
SDHD

Answer 33

• Pheochromocytoma and paraganglioma syndromes
• SDHA, SDHB, SDHC, SDHD: Paragangliomas, pheochromocytomas
• SDHB, SDHC, SDHD: Familial renal cell carcinoma
• SDHB, SDHD: Infrequent cause of Cowden syndrome
• SDHA, SDHC, SDHD: Gastrointestinal stromal tumor

Question 34

WRN (aka. RECQL2)

Answer 34

• Werner syndrome
• Associated with progeria (premature aging) after puberty and cancer predisposition (10%
  lifetime risk), mostly sarcomas

Question 35

IRAK4

Answer 35

• Interleukin receptor-associated kinase (IRAK) 4
  deficiency: Impaired IL-1 receptor and Toll-like receptor
  function, and impaired NFκB pathway activation in
  neutrophils
• Associated with severe, recurrent infections, no response to LPS, IL-1, or IL-18 (proinflammatory cytokines)

Question 36

SLC35C1

Answer 36

• LAD type 2: Normal CD11b/18 but defective CD15s
  (sialyl Lewis X) and Bombay Phenotype
• Bombay phenotype: Lacks H antigen. Patients are
  universal donors but can only accept blood from other
  Bombay patients
• Only about ten patients described worldwide

Question 37

GLUT1

Answer 37

• Infantile hemangioma
• 20% of angiosarcoma

Question 38

GNAQ

Answer 38

• Congenital hemangioma: Present at birth and different from infantile hemangioma
• Rapid involution, partial involution, and no involution
• Associated with consumptive coagulopathy
• GLUT1 negative

Question 39

NBEAL2

Answer 39

• Gray platelet syndrome: Rare macrothrombocytopenia with reduced α-granules in platelets
• Associated with mild to moderate bleeding and myelofibrosis

Question 40

PIEZO1

Answer 40

• Hereditary xerocytosis: Stomatocytosis with abnormally dehydrated RBCs due to a cation channel defect (channelopathy)
• Gain-of-function mutations
• Causes a hemolytic anemia that can be mistaken for hereditary spherocytosis and iron overload

Question 41

PLAU

Answer 41

• Quebec platelet syndrome: Gene duplication
• Rare macrothrombocytopenia syndrome
• Massive increase in urokinase-type plasminogen activator (UPA) within platelets that leads to increased fibrinolysis
• Mild thrombocytopenia
• Delayed bleeding after surgery, avoided if fibrinolytic inhibitors

Question 42

LAD