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Rotation - Molecular > Required Readings > Flashcards

Required Readings Flashcards

1
Q

What are the two functional classes of balanced chromosomal rearrangements in cancer?

A

Aberrations that result in the formation of a chimeric fusion gene with new or altered activity

Aberrations that result in deregulated expression of a structurally normal gene

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2
Q

What types of tumors have the strongest association with chromosomal rearrangement?

A

Hematologic cancers

Tumors of mesenchymal origin

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3
Q

What are the two major classes of genes which form chimeric fusion products?

A

Tyrosine kinase genes (eg ABL1)

Transcription factor genes (eg FLI1)

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4
Q

Besides CML, what tumors express ABL fusions sensitive to small molecule RTK inhibitors?

A

T-cell ALL

(ABL1-NUP214)

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5
Q

What are the two classic translocations seen in Ewing sarcoma?

A

t(11;22)(q24.1-q24.3;q12.2)
EWSR1-FLI1

t(21;22)(q22.3;q12.2)
EWSR1-ERG

(both FLI1 and ERG are part of the ETS family of transcription factors)

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6
Q

Describe the classic genetic change and gene fusion product:

NSCLC

A

inv(2)(p22-p21p23)

EML4-ALK

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7
Q

Describe the classic genetic change and gene fusion product:

Anaplastic large cell lymphoma

A

t(2;5)(p23;q35)

ALK-NPM1

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8
Q

Describe the classic genetic change and gene fusion product:

Multiple myeloma

A

Several with IgH…

t(4;14) - WHSC1
t(6;14) - Cyclin D1
t(11;14) - Cyclin D3
t(14;16) - MAF
t(14;20) - MAF

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9
Q

Describe the classic genetic change and gene fusion product:

CML

A

t(9;22)(q34.1;q11.23)

BCR-ABL1

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10
Q

Describe the classic genetic change and gene fusion product:

Myeloid neoplasms associated with eosinophilia
(two!)

A

del(4)(q12q12)
FIP1L1-PDGFRA

t(5;12)(q31-q32;p13)
PDGFRB-ETV6

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11
Q

Describe the classic genetic change and gene fusion product:

Papillary thyroid cancer
(Two!)

A

inv(10)(q11.2q11.2)
RET-NCOA4

inv(10)(q11.2q21)
RET-CCDC6

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12
Q

Describe the classic genetic change and gene fusion product:

Acute megakaryoblastic leukemia

A

t(1;22)(p13;q13)

RBM15-MKL1

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13
Q

Describe the classic genetic change and gene fusion product:

Follicular thyroid carcinoma

A

t(2;3)(q12-q14;p25)

PAX8-PPARG

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14
Q

Describe the classic genetic change and gene fusion product:

Prostatic adenocarcinoma

A

del(21)(q22.3q22.3)

TMPRSS2-ERG

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15
Q

Describe the key chromosomal imbalance and the gene it involves for:

Breast cancer

A

amp(1)(q32.1)

IKBKE

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16
Q

Describe the key chromosomal imbalance and the gene it involves for:

Neuroblastoma

A

amp(2)(p24.1)

MYCN

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17
Q

Describe the key chromosomal imbalance and the gene it involves for:

Malignant melanoma

A

amp(3)(p14.2-p14.1)

MITF

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18
Q

Describe the key chromosomal imbalance and the gene it involves for:

Polycythemia vera

A

+9p

JAK2

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19
Q

Describe the key chromosomal imbalance and the gene it involves for:

NSCLC

A

amp(14)(q13)

NKX2-1

20
Q

Describe the key chromosomal imbalance and the gene it involves for:

Renal cell carcinoma

A

del(3p26-p25)

VHL

21
Q

Describe the key chromosomal imbalance and the gene it involves for:

Colon cancer
(Two!)

A
  • *del(5)**(q21-q22)
  • *APC**
  • *del(4)**(q12)
  • *REST**
22
Q

Describe the key chromosomal imbalance and the gene it involves for:

Retinoblastoma

A

del(13)(q14.2)

RB1

23
Q

Describe the key chromosomal imbalance and the gene it involves for:

Wilm’s tumor

A

del(X)(q11.1)

FAM123B

24
Q

What are some translocation partners for c-MYC in Burkitt’s lymphoma?

A

14q, 22q, 2p

25
Q

What aberrations can occur as initiating events?

Which can occur as progression events?

A

Initiating: Translocations & mutations

Progression: Translocations, mutations, & amplifications

26
Q

What are the six categories of oncogenes (by gene product?

A

Transcription factors

Chromatin remodelers

Growth factors

Growth factor receptors

Signal transducers

Regulators of apoptosis

27
Q

What is the effect of EWS gene fusion?

A

When EWS is fused to a DNA-binding domain, it greatly stimulates gene transcription.

28
Q

Describe the tumorigenic effect of TMPR fusion in prostate cancer.

A

TMPR522 has an androgen responsive promoter element; when fused with an ETS gene (ETV1, ERG1) it increases proliferation and inhibits apoptosis of prostatic glandular cells.

29
Q

What are the two kinds of enzymes which remodel chromatin? How do they contribute to tumorigenesis?

A
  1. ATP-dependent enzymes that move the positions of nucleosomes.
  2. Enzymes that modify the N-terminal tails of histones.

*Both cause epigenetic modification that determines chromatin’s transcriptional capacity

30
Q

Describe MLL’s contribution to tumorigenesis in AML and ALL.

A

MLL is a very large complex including components of transcription complexes and histone methylators. Its fusion with one of many proteins causes deregulation of homeobox genes (encoding transcription factors), EPHA7 (which encodes an RTK), and microRNAs.

31
Q

What is the normal function of PDGF?

How is it implicated in cancers?

A

Consisting of alpha and beta chains, it is released by platelets to induce proliferation in wound healing.

Overexpression results in unregulated cell growth. Also, the sis oncogene of simian sarcoma virus is structurally similar to the beta chain.

32
Q

How do WNT/APC/beta-catenin contribute to tumorigenesis.

A

Beta-catenin is involved in cell-cell adhesion and activation of several pathways. WNT inhibits its phosphorylation while APC promotes it. Increase in WNT or loss of APC results in inhibited degradation of beta-catenin, which translocates to the nucleus, promoting genes involved in proliferation & invasion.

33
Q

Describe EGFR’s contribution to tumorigenesis.

What drugs are targeted against it?

A

A deletion of the ligand-binding domain results in constitutive activation of the receptor, triggering several pathways via an RTK element.

Antibodies against the extracellular domain (eg Cetuximab) and competitive inhibitors of the RTK element (erlotinib/gefitinib)

34
Q

What are the two main groups of signal-transducer oncogenes?

A

Nonreceptor protein kinases (eg RTKs and serine/threonine kinases)

GTP-binding proteins

35
Q

Describe the two main pathways that lead to apoptosis.

A

Stress pathway: BCL2 homology 3 (BH3) domain inactivates BCL-2 >> Bax releases caspases.

Death receptor pathway: Fas ligand / TNFa activates surface death receptors.

36
Q

What 3 mechanisms can result in oncogene activation?

A

Chromsomal rearrangements (gene fusion or deregulation)

Mutations

Gene amplifications

37
Q

Describe RAS oncogenes roles in tumorigenesis.

Distinguish K-RAS and N-RAS.

A

When mutated, RAS genes encode a continuously active protein that transduces growth signals.

K-RAS: Lung, colon, pancreas.

N-RAS: AML, MDS

38
Q

Describe the role of BRAF mutations in tumorigenesis.

Which tumors is it mutated in?

A

V600E (or V599E?) within the kinase domain causes constitutive activity, triggering the MAP kinase cascade.

Seen in melanoma, some colorectal & liver, thyroid, and gliomas.

39
Q

Recall four different oncogene families that are often amplified in cancers.

A

MYC

CCND1

EGFR (eg Her2)

RAS

40
Q

What genetic aberrations usually trigger hematopoietic tumors, soft tissue sarcomas, and carcinomas?

A

Hematopoietic tumors: Activation of an oncogene

Soft-tissue sarcomas: Activation of an oncogene

Carcinomas: Loss of function of a tumor suppressor

41
Q

What is the structure and function of microRNA genes?

A

Encodes RNA strands 21-23 nucleotides long which regulate gene expression by silencing mRNA.

42
Q

How can abnormal expression of miRNA result in tumorigenesis?

A

Upregulation of genes that down-regulate tumor suppressors

Downregulation of genes that down-regulate oncogenes

43
Q

What microRNAs are implicated in MLL+ AML?

In DLBCL?

A

MiR191 (upregulated via MLL fusion)

MiR155 (also in breast, lung, and colon cancers)

44
Q

Recall the pathogenic contribution of the following miRNAs:

LET7 family

MiR15a & miR-16-1

MiR21

A

LET7 normally targets RAS and is deleted in lung cancers.

miR15a and miR-16-1 target BCL-2 and are downregulated in CLL.

MiR21 suppresses PTEN and is overexpressed in many cancers.

45
Q

What levels of evidence support type I and II genomic variants?

A

I: Level A (predicts resistance to FDA-approved therapies) or Level B (predicts response/resistance based on well-powered studies)

II: Level C (responds/resistance to FDA therapy of a different tumor) or Level D (plausible therapeutic significance based on preclinical studies)

Rotation - Molecular (4 decks)

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