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Flora Ross > Chromosomes > Flashcards

Chromosomes Flashcards

1
Q

2 critical genes for 1q21 recurrent region?
Clinical features

A

GJA5 & GJA8

Variable expressivity (dev delay, TOF, varying head size depending on del/dup) & incomplete penetrance

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2
Q

Phenotype of 1q21 del +TAR region 2.7Mb inc RBM8A?

A

Absent radii with thumbs and thrombocytopenia.

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3
Q

Chr1 abn seen in Multiple Myeloma

A

1q gain/1p del

CKS1B (1q) promotes cell cycle - poor prognosis

CDKN1C (1p) tumour suppressor - worse overall survival

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4
Q

Difference between t(1;19) and t(17;19) in B-ALL?

A

t(1;19) PBX1::E2A has better prognosis than t(17;19) HLF::E2A

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5
Q

Oligodendroglioma chr1 abn

A

1p/19q co-deletion / unbal t(1;19) - improved prognosis and responsiveness to therapy

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6
Q

2 examples of N-MYC abnormalities

A

t(2;8) IGK::MYC variant in DLBCL

N-MYC (2p24) amplification in neuroblastoma - aggressive tumour

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7
Q

Chr band for recurrent deletion involving DLG1

A

3q29

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8
Q

Somatic abn at 3q26.2

A

EVI1/MECOM (3q26.2) in AML/B-ALL. 3q rearrangements are typically t(3;3) or inv(3) but hard to ID on G-banding.

t(3;21) MECOM::RUNX1 seen in AML/MDS. Generally associated with poor prognosis

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9
Q

Chr4 CNV syndrome

A

Wolf-Hirschhorn syndrome

300-400kb critical region 4p16.3. Can be terminal or interstitial. 90% = de novo. 45% = unbalanced translocation (either de novo or inherited). Common is a der(4)t(4;8)

Greek warrior helmet face, dev delay, FTT, hypotonia, seizures, midline fusion defects

Genes: FGFR3, NSD2 LETM1, NAT8L

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10
Q

FSHD1 mechanism

A

Deletion/contraction of D4Z4 repeats at 4q35 + hypomethylation + >1 permissive 4qA genotype - this allows expression & accumulation of DUX4 protein = muscular dystrophy/weakness descending from face to upper body to lower limbs

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11
Q

Result of CHIC2 (4q12) deletion and implications for disease

A

CHIC2 (4q12) deletion = FIPL1::PDGFRA, GOF TK activity in ALL & eosinophilia. Sensitive to TKIs e.g. imatinib

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12
Q

Common cytogenetic abn in infant ALL (<1yo)

A

t(4;11) KMT2A::AFF1
High risk and poor prognosis

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13
Q

5p deletion syndrome

A

Cri du chat (5p-) syndrome

Mostly terminal 5-40Mb, high no of repetitive sequences accounting for instability

80%= de novo, 15%=unbalanced trans

High pitch cry, microcephaly, severe neurological deficits, hypotonia

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14
Q

5q syndrome deletion

A

Sotos syndrome (5q35 deletion)

Haploinsufficiency of NSD1 a histone methyltransferase that regulates genes involved in development. 95% =de novo

Overgrowth disorder (cerebral gigantism, high bone age, LD, hypotonia, behavioural issues and seizures)

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15
Q

2 examples of chr5 abn in myeloid malignancies

A

del(5q) in AML/MDS
Sole abn MDS = favourable
Usually part of complex ktype AML = poor prognosis

NPM1 (5q35.1) mutations associated with improved outcomes in AML but depend on presence of FLT3-ITD e.g. NPM1-mut+FLT3-WT=good prognosis. Mutations make NPM1 stuck in cytoplasm

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16
Q

What is UPD(6)pat associated with?

A

Neonatal benign transient diabetes due to overexpression of paternal genes at 6q24

Low birth weight, normal development, resolved by 3y

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17
Q

46,XX DSD example on chr6

A

Congenital adrenal hyperplasia. 21 hydroxylase deficiency

Recessive

CYP21A2. Has a pseudogene so difficult to sequence

Also has other genes involved (multiple genes leading to one similar phenotype)

Utility in prenatal setting to test as can treat XX females with dexamethasone to prevent virilisation

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18
Q

Describe the Williams syndrome deletion

A

7q11.23. Deletion of 1.5-1.8Mb

28 genes inc ELN

Mediated by NAHR between LCRs

Difficult to define prenatally. “Cute” face, dev delay, hypotonia and joint laxity

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19
Q

AR disorder that UPD(7) may have implications for

A

Cystic fibrosis - CFTR

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20
Q

What IPSS prognosis is -7 or del(7q) in MDS?

A

Usually secondary to treatment. Poor IPSS prognosis (if not secondary)

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21
Q

What is EGFR and how is it targeted in NSCLC?

A

EGFR is a transmembrane receptor for EGF ligands, has TK activity

Overexpression or hyperactivation in NSCLC increases cell signalling

Target EGFR activating muts with TKI

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22
Q

Name of mosaic trisomy 8 syndrome

A

Warkany syndrome is associated with skeletal abnormalities, facial dysmorphism, LD, cardiac/renal anomalies and increased risk of haem malignancy

Diagnosis on cultured fibroblasts or skin biopsy

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23
Q

Most common MYC (8q24) translocation in B cell lymphoma? Oncogenic mechanism?

A

t(8;14) IGH::MYC in 80% of Burkitts

IGH is always switched on so the fusion activates MYC oncogenic upregulation of cell proliferation genes

Rarer variants include t(2;8) IGK and t(8;22) IGL

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24
Q

What is the most common cyto abnormality in childhood AML?

A

t(8;21) RUNX1T1::RUNX1

Intermediate prognosis

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25
Q

Most frequent additional cyto abnormality in CML?

A

+8 most frequent additional abn in CML but no affect on prognosis if in isolation with t(9;22)

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26
Q

Describe Kleefstra syndrome

A

9q34 subtelomeric deletion 0.7-1.3Mb

Dev delay, coarse facial features, behavioural issues

75% de novo deletion,

HI of EHMT1 an epigenetic regulator that affects gene transcription by histone modification

27
Q

ABL1 function and 2 example rearrangements

A

ABL1 fusion genes are constitutively active TK, target with TKI e.g. imatinib

t(9;22)(q34;q11) BCR::ABL1 diagnostic for CML

ABL1 rearr with other partners in ALL, most commonly ETV6 t(9;12)

28
Q

Significance for MGMT (10q) promoter hypermeth in glioblastoma?

A

Impaired DNA repair of O6-methylguanines
= increased mismatches
= apoptosis

Predicts improved response to chemo inducing DNA damage as it cannot be repaired effectively

29
Q

Describe the 2 imprinted syndromes at 11p15.5

A

BWS (loss of mat imprinting): ICR2 hypometh, ICR1 hypermeth, UPD(11)pat, dup/del, CDKN1C muts, mosaic pat unidiploidy

RSS (loss of pat imprinting): ICR1 hypometh, dups/del. UPD(11)mat rare but UPD(7)mat in 4-10% of cases

30
Q

2 chr11 deletion syndromes

A

WAGR 11p13 deletion (min=700kb)
PAX6 & WT1

Jacobsen syndrome 11qter deletion (5-16Mb)
15% = unbal trans

31
Q

Function of KMT2A?

A

KMT2A is a methyltransferase and global regulator of transcription. When constitutively active, it activates HOXA cluster genes = aberrant histone modification. There are usually no co-operating muts

11q23 rearr in AML and ALL usually poor prognosis

> 100 partners

32
Q

Example KMT2A rearrangements in ALL and AML

A

ALL

Common in infants <1y with CNS involvement
t(4;11)(q21;q34) ::AFF1
t(11;19)(q;23;p13) ::MLLT1

AML

6 common partners, all poor prog apart from t(9;11) ::MLLT3 which is intermediate

33
Q

What is the syndrome associated with mosaic +i(12(p10)? Clinical features?

A

Pallister-Killian, mosaic tetrasomy 12p

Variable phenotypes, does not correlate with level of mosaicism

Prenatal: diaphragmatic hernia

Postnatal: hypotonia, speech delay, dysmorphic face, abn skin pigmentation, seizures, VSD

34
Q

Example Rasopathy: gene, clinical features and mechanism

A

Noonan syndrome

CHD, dysmorphic face, short stature, dev delay, increased risk of JMML, webbed neck, cryptoorchidism

RAS-MAPK signalling is a mediator of early/late developmental processes

PTPN11 (50% of cases) is a SHP2 protein critical for heart, blood cells and bone. Normally GOF missense

Somatic PTPN11 muts in 30% of JMML patients

35
Q

Common cytogenetic abnormality involving chr12 in ALL?

A

t(12;21)(p13;q22) ETV6::RUNX1

15-35% of B-ALL children (not infants/adults)

Frequently cryptic on karyotype, confirm by FISH

ETV6 is highly expressed so the fusion genes = constitutive activation of RUNX1 transcriptional repressor of haematopoesis

36
Q

KRAS function and implications of mutations in metastatic CRC

A

KRAS is an oncogene. GOF muts prevent intrinsic GTPase so GTP signalling is increased and EGFR/MAPK pathways upregulated

In CRC, if a KRAS mut is present there is unlikely to be a response to EGFR monoclonal antibodies e.g. Cetuximab that target upstream

37
Q

Hereditary cancer syndrome associated with a deletion on 13q?

A

Retinoblastoma RB1

Cancer of retinal sensory cells usually in infants <3y

RB1 is a TS that controls G1 to S phase transition. AD SNV/deletion + 2nd somatic hit

40% have germline muts (esp if bilateral or FHx)

38
Q

Why is FLT3 testing urgent for diagnostic AML patients?

A

FLT3 has a complex repetitive element that can result in an Internal Tandem Duplication (ITD) or SNVs within the kinase domain

URGENT testing at Dx as kinase inhibitors e.g. midostaurin must be incorprorated by day 8

Muts increase receptor activation and downstream proliferation pathways

Prognostic impact depends on presence or absence of favourable NPM1-mut. But generally FLT3 mut = poor prognosis

39
Q

UPD(14) example

A

Maternal UPD = Temple syndrome

Pre/postnatal growth retardation, may be mild/undiagnosed. Robertsonian trans carriers have increased risk of UPD(14)

14q32 = imprinted region; UPD = unmeth MEG3-DMR

40
Q

14q32.22

A

IGH cluster region involved in many translocations in haem malignancies. Fused genes are under regulatory control from the highly expressed IGH cluster

t(14;18) ::BCL2 - Follicular & DLBCL
t(11;14) ::CCND1 - CLL & Mantle Cell
t(4;14) ::FGFR3 - Myeloma, decreased OS
t(14;16) ::MAF - Myeloma, high risk
t(8;14) ::MYC - >80% Burkitts

When present in FL/DLBCL it is important to also assess BCL2/BCL6 as 2/3 hits have worse prognosis

41
Q

2 recurrent CNV syndromes for chr15

Associated phenotype?

A

15q11.2 BP1-BP2, NIPA1

15q13.3 BP4-BP5, CHRNA7

Neurosusceptibility locus

42
Q

2 recurrent CNV syndromes for chr16

A

16p11.2 BP4-BP5, TBX6

16p13.11 BP2-BP3, MYH11

43
Q

Favourable AML chr16 cyto abn?

A

Inv(16) or t(16;16) = CBFB::MYH11

44
Q

17p12 gene and 2 associated disorders

A

PMP22

Deletion = HNPP
Duplication = CMT

45
Q

17p11.2 gene and 2 associated disorders

A

RAI1

Deletion = Smith-Magenis
Duplication = Potocki-Lupski

46
Q

Cause of Miller-Dieker syndrome and clinical features

A

17p13.3 deletion involving LIS1

Lissencephaly (smooth brain), dev delay, ID, seizures, microcephaly

47
Q

Function of TP53

A

Guardian of the genome, gatekeeper of cell cycle. Mediates G1 arrest in response to DNA damage allowing repair or apoptosis

48
Q

Where is TP53 located?

A

17p13

49
Q

How frequently is TP53 mutated in cancer?

A

50%

50
Q

What predisposition to cancer syndrome are germline TP53 variants associated with?

A

Li Fraumeni

51
Q

Translocation & fusion gene found in APML

A

t(15;17)(q24;q21) PML::RARA

52
Q

Prognosis of APML

A

Favourable if treated immediately. High risk of complications due to low platelets and bleeding risk (DIC)

53
Q

How is APML treated? Cure rate? Complication?

A

Retinoic Acid Receptor Alpha (RARA) muts are targeted with ATRA to induce differentiation and combined with arsenic trioxide chemotherapy to trigger apoptosis

90% 10 year survival

Differentiation syndrome

54
Q

Germline chr18 disorder

A

Pitt-Hopkins - HI of TCF4
Severe epilepsy, dev delay and breathing abnormalities

55
Q

Somatic chr18 example

A

t(14;18)(q32;q21) IGH::BCL2

56
Q

Function of BCL2

A

BCL2 is an anti-apoptosis protein, overexpressed due to fusion with IGH promoter. In germinal centre = Follicular lymphoma

57
Q

Alagille syndrome features

A

HI of JAG1 at 20p12
Liver, skeleton, heart, eye abn and facial dysmorphism

58
Q

Example of an IPSS good prognosis cytogenetic abnormality in MDS

A

del(20q)

59
Q

What % of trisomy 21 are Robertsonian?

A

5% (de novo or inherited)

60
Q

2 examples of chr21 in B-ALL

A

t(12;21) favourable prog

iamp(21) high risk, good prog with intensive treatment

61
Q

Germline chr22 examples

A

22q11.2 deletion syndrome

Emanuel syndrome der(22)t(11;22)(q23.3;q11.2)

62
Q

What 2 syndromes are associated with LCR22 A-D deletions? Size of deletion?

A

DiGeorge and Velo-Cardio-Facial

~3Mb

63
Q

22q11.2 haploinsufficient gene

A

TBX1

64
Q

2 examples of somatic chr22 abn

A

t(9;22)(q34;q11) BCR::ABL1 in CML

t(11;22)(q24;q12) FLI1::EWSR1 in Ewing sarcoma

Flora Ross (12 decks)

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