Chapter 7 Flashcards by Hanne Moberg

What is the Philadelphia chromosome?

A chromosome generated by a gene translocation causing chronic myeloid leukaemia. It is created by reciprocal translocation of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1.

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Explain Knudsons two-hit theory?

Individuals that have inherited one mutant allel presented with a disease frequency consistent with a single somatic mutation, while individuals without a mutant allele exhibited age-onset patters consistent with 2 somatic mutations.

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Name all the known oncogenes (15)?

p110-alpha, EGFR, HER2 (ERBB2), B-RAF, K/N/H-RAS, MYC, BRC-ABL, IDH1&2, JAK2, KIT, MET, FLT-3

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p110-alpha: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene, breast, prostate, colorectal, cervical, head and neck gastric and lung

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MYC: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene, LSA, FeLV

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B-RAF: Oncogene or tumour suppressor, associated with which type of neoplasia and targeted treatment therapy?

Oncogene; TCC, prostatic carcinoma vemurafenib

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K-RAS: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; pancreatic, lung, colorectal, endometrial, ovarian

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H-RAS: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; bladder

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N-RAS: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; lymphoma

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KIT: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; GIST, AML, melanoma, mast cell tumour

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EGFR: Oncogene or tumour suppressor, associated with which type of neoplasia, targeted treatment therapy?

Oncogene; 
Feline mammary carcinoma (HER-2) 
AGASAC 
OSA (HER-2 overexpression) 
TCC (HER-2 overexpression) 
Gastric carcinoma (HER2)  cetuximab

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HER2: Oncogene or tumour suppressor, associated with which type of neoplasia and targeted therapy?

Oncogene; breast, gastric, ovarian, bladder; trastuzumab, lapatinib

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BCR-ABL: Oncogene or tumour suppressor, associated with which type of neoplasia, targeted therapy treatment?

Oncogene; CML, ALL, AML; imatinib, dasatinib, nilotinib

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IDH-1: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; glioblastoma, AML

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IDH-2: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; glioblastoma, AML

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JAK2: Oncogene or tumour suppressor, associated with which type of neoplasia? Tx options -

Oncogene; PV, MCT, Ruloxitinib, olcacitinib licences in dogs for skin tx

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MET: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; OSA
Felina mammary carcinoma
ACASAC

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FLT-3: Oncogene or tumour suppressor, associated with which type of neoplasia?

Oncogene; AML

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P53: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS;
SCC 
OSA 
Perianal adenoma/carcinoma 
Canine adenocarcinoma 
Stertoli cell tumour 
TVT

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PTEN: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; 
OSA 
Melanoma 
HSA 
HS 
MCT

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p16ink4a: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; Melanoma, pancreatic, lung, bladder, head and neck, colorectal, breast

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p14arf: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; Lung, bladder, head and neck, colorectal, breast

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BRCA 1&2: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; Breast and ovarian

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LBK1: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; lung, GI, pancreatic, cervical, melanoma,

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VHL: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; Kidney, adrenal, hemangioblastoma

APC: Oncogene or tumour suppressor, associated with which type of neoplasia?

TS; Colorectal, gastric

FBXW7: Oncogene or tumour suppressor, associated with which type of neoplasia?

Tumor suppressor gene; ALL, bile duct, colorectal, gastric, endometrial, lung, prostate, pancreatic, ovarian

Rb: Oncogene or tumour suppressor, associated with which type of neoplasia?

Tumor suppressor gene; retinoblastoma, lung, bladder, oesophageal, osteosarcoma, glioma, liver, CML, prostate, breast

NF1: Oncogene or tumour suppressor, associated with which type of neoplasia?

Tumor suppressor gene; Neurofibroma, neuroblastoma, glioma, colorectal

NF2: Oncogene or tumour suppressor, associated with which type of neoplasia?

Tumor suppressor gene; meningioma, schwannoma, glioma

What are the hallmarks of cancer?

self sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, genomic instability, deregulated metabolism, capacity for invasion and metastasis. Avoid immune clearance and stimulation of inflammation

Name 6 examples of gain of function events?

BCR-ABL, MYC, EGFR/ERRB2, PI3 kinase, RAS/RAF, IDH

Name 4 examples of loss of function events?

p53, PTEN, BRAC1/BRAC2, retinoblastoma protein

T or F: PI3 Kinases tend to become up-regulated in neoplastic processes?

False- they become downregulated

What is the most common B-RAF gene mutation?

V600E substitution in the kinase activation loop

Which drug is used specifically to treat the V600E substitution mutation in the B-RAF gene?

vemurafenib

For which human malignancy has the used of vemurafenib improved the outcome, and for which mutation is the drug intended?

Malignant melanoma, B-RAF mutation which is found in 90% of malignant melanoma.

Which gene is encoding for p53 protein?

TP53

What is the most common mutation in the TP53 gene?

Missense substitutions

Which germline mutation leads to Li-Fraumeni syndrome`

Germline mutation in P53

What is the mechanism of action of imatinib?

It is an BCR-ABL inhibitors used for treatment of CML

Which drug has been used to effectively downregulate oncogenic RAS?

There is no such drug found.

What are gatekeepers?

Generally tumour suppressors which constrain growth by regulating cell cycle progression and activating anti-apoptotic mechanisms

What are caretakers?

DNA repair proteins, impede oncogenesis by preventing genetic instability

What are landscapers?

Alterations in stroll cells which promote tumorigenesis

Carcinogenesis may initiated and promoted by changes a variety of genetic mutations, however the mutations may also influence the cell on different levels such as:

epigenetic, mRNA stability, non-coding RNa, roeomic changes such as ubiquination and metabolic changes which synergistically promote carcinogenesis

Give 3 examples of gene mutations resulting in altered gene expression and carcinogenesis:

1) BCR-ABL - reciprocal translocation between 22 and 9 2) translocation between 14 and 18 - bring the BCL2 gene under control of IgG gene enhancer - the cell becomes resistant to cell death signals 3) recombination between 9 and 12 found in CML and ALL resulting in active TEL-JAK which increases cell proliferation, survival and differentiation.

Give an example of gene amplification in carcinogenesis?

HER-2 (ERBB2) or MYC in breast cancer, result in hyper-activated oncogenic pathways

which changes on an epigenetic level may promote tumorigenesis?

DNA methylation, pattern of acetylation , methylation and phosphorylation of DNA associated histones (called the histone code)

Methylation of the CpG dinucleotides result in silencing of the gene

How can hypomethylation of DNA contribute to carcinogenesis

Methylation of DNA normally prevent movement of transposable elements in DNA to prevent genomic instability. When DNA becomes hypomethylated it may contribute to genomic instability.

What is microRNA?

20-30 nucleotide RNA molecules, generated by defined posttraslation maturation steps. Bind with mRNAt transcripts to block gene expression.

What is the result of the Philadelphia gene?

the BCR-ABL fusion gene result in a constitutively active tyrosine kinase permanently located in the cytoplasm. It will activate multiple downstream pathways and increase genomic instability.

Give an example of a mutation that will cause loss and gain of function in the cell?

IDH 1 and 2

Explain the normal function of p53?

Normally, the level of P53 will be kept low by MDM2, marking it for proteasome mediated degradation. When the cell undergoes oncogenic stress, increased activity of P14 inhibits MDM2, and p53 will accumulate in the cell. It works mainly as a transcription factor increasing gene expression of genes involved in apoptosis or cell cycle arrest and DNA repair.

A germline mutation in P53 will result in which human syndrome?

Li-Fraumeni syndrome = tumour development in multiple tissues

what is the role of p21 in P53 regulation?

When stabilised due to oncogenic stress, P53 increase transcription p21 P21 has a high affinity for G1 CDK/cyclin complex and act as.a CDK1 inhibiting kinase activity = arresting cells in G1

What are miRNA and how do they impact carcinogenesis?

They are small sequences of non-coding RNA which regulate gene expression and can impact cardiogenesis by reducing gene expression

How does gene amplification promote tumorigenesis?

By increasing copy numbers of an oncogene increasing the oncogene dosage of that gene

Give an example of change in protein level which causes tumour progression?

Majority of viral causes of tumorgenesis interfere with the cells regulator proteins such as p53. Ex. papillomavirus

Chapter 7 Flashcards

(60 cards)