CANCER GENETICS EXAM 1

protooncogenes

can be turned on or off to regulate the cell cycle

mutant forms of protooncogenes that are permanently switched on are called

oncogenes

oncoproteins change gene expression patterns directly or indirectly

to turn on cell proliferation

peyton rous

transmits sarcoma development from affected chickens and unaffected chickens using filtered tumor extract 

expresses mutant version of tyrosine kinase src to turn on cell cycle

RSV

multiple modes of protooncogene activation

point mutation, gene amp, chromosomal translocation, local DNA rearrangements, insertional mutagenesis 

protein coding-point mutation example

Ras oncoprotein blocks release of phosphorylation continually activating downstream of serine threonine. mutates GLY to VAL

chemotherapeutic agents that target members of the ras pathway

nib=kinase inhibitor, mab=monoclonal antibody

gene amplification example

human epidermal growth factor, HER2 amplicons can have up to 500 copies of the gene resulting in high levels of the receptor protein at the cell surface. onion skin replication, triggors oncoprotein pathways including RAS and SRC

chemotherapy for HER2

receptor dimerization and tyrosine kinase of her2 targeted 

chromosomal translocation example

Philadelphia chromosome, chromosomes 9+22 translocation resulting in the generation of a protein that fuses BCR with ABCL. 

drug that targets BCR and ABCL functions

imantin b/ Gleevac

insertional mutagenesis

upregulation of MYC expression, insertion of viral DNA places cell gene under regulation of viral gene expression. too much protein is made

gatekeeper tumor suppressor gene 

control cell growth directly

caretaker tumor suppressor gene

maintain stable genome

landscaper tumor suppressor genes

maintain normal tissue structure

landscaper example

SMAD4 
regulator of development and tissue homeostasis

caretaker example

p53 controls cell cycle and dna repair

gatekeeper example

APC mutations allow for more beta catenin

6 hallmarks that get mutated in a cancer cell

controlled cell proliferation, growth suppressing signals, control of cell movement, finite cell replication, limited angiogenesis, appropriate cell death

density dependent cell division inhibition

cell growth is limited by presence of surrounding cells in a monolayer; tumor cells have lost their ability to sense neighboring cells and just pile on top of each other.

what protein signals contact inhibition

HIPPO

substrate dependent contact inhibition

cancer cells grow well even when cells are suspended due to decreases in syndecans-4

extending the hayflick limit

increase in telomerase

cell cycle protein mutation

rb is always phosphorylated so E2F can stay active

heart of tumor development

control of DNA damage

BRCA-1

involved in DNA repair, one mutant allele in inherited breast cancer

hypertrophy

increase in cell size, normal organization

hyperplasia

increase in cell #, normal organization

dysplasia

disorganized growth

neoplasia

disorganized growth, increase in the number of dividing cells

tumors are ____ in nature meaning the mass originates from the same cell

monoclonal

characteristics of a benign tumor

local growth, slow growth, well differentiated, rarely terminal

characteristic of a malignant tumor

metastatic, slow or rapid, variable differentiation, often terminal

tumor angiogenesis

increase activators, reduce inhibitors to vascularize the cell leading to increase growth and invasion of the cell.

father of angiogenesis

judah folkman

iressa angiogenesis targeted drug

blocks production of VEGF

Avastin angiogenesis targeted drug

neutralizes VEGF

Sutent angiogenesis targeted drug

blocks receptors for VEGF and other angiogenesis stimulators

invasion

migration into local tissues

Metastasis

cancer entering through the bloodstream

p53

transcription factor that senses stress signals, DNA damage triggers activation and suppresses tumors

rb

tumor suppressor, cell cycle controller, transitions cell cycle through phosphorylation of the receptor allowing E2F to unbind

ETS/TCF

binding motif, catalytic subunit of telomerase

TWIST

controls gene expression, controls epithelial cells and their functionality

EMT

we want it during development but not after

control of cell death

mutations that repress apoptosis allow damaged cells to survive and evolve

syndecan 4 levels in colon cancer vs breast cancer

breast cancer is up, colon cancer is down

carcinoma

epithelial cells

sarcoma

supporting tissue

lymphoma 

lymph nodes-leukemia 

benign naming

oma

malignant naming

general type orgin

chemical carcinogenesis

chemical induced cancerous transformation of normal cells

benzo(a)pyrene

in cigarette smoke, metabolized in numerous tissues creating the reactive species that binds to guanine causing DNA distortion

Asbestos 

enters the lungs and penetrated into the chest cavity causing chronic inflammation 

What does asbestos inflammation lead to 

leads to the development of mesothelioma, inflammatory leukocytes cause oxidative stress, causing DNA adducts interfering with mitosis, stimulating proliferation. 

Aflatoxin

toxic chemicals produced by mold aspergillus, requires metabolic activation

what does aflatoxin do to the liver

promotes excessive necrosis leading to scarring and abnormal liver nodules. as they worsen p53 is lost and telomerase is activated in a hepatocellular carcinoma.

initiation of a hepatocellular carcinoma

introduction of a mutation by a carcinogen

promotion of a hepatocellular carcinoma

prolonged stimulation of proliferation in damaged cells 

progression of a hepatocellular carcinoma 

evolution and selection of more aggressive and invasive cells 

phorbol ester

mimics the binding properties of DAG, binding to protein kinase C, continually activating cell division

the AMES test

bruce ames, accounted for possible procarcinogenic nature of chemicals by expressing to liver enzymes

nucleotide excision repair

pyrimidine dimers repaired by activation of p53

Peyton Rous

transmitted sarcoma from affected chickens to healthy chickens by using filtered tumor extract

peter vogt and duesberg

perform focus forming assays with RSV

retrovral oncogenes

mutant forms of protooncogenes

viral oncogenes

evolved overtime to function without control during cell proliferation

Rous Sarcoma 

mutant version of tyrosine kinase src to turn on the cell 

viral src

lost regulatory phosphorylation site at amino acid 527, therefore it is always on

activated vsrc

promotes cell survival and proliferation

example of DNA virus that express oncoprotein that induce cell proliferation

HPV- E6 binds p53 preventing DNA repair, E7 binds to Rb preventing the association with E2F resulting in cell proliferation

HPV 16,18

associated with cervical cancer, viral dna integration affects E2 which controls the expression of e6 and e7

example of a favorable microenvironment

prostate cancer and bone environment. tumor stimulates osteoblast and osteoclast growth factors that stimulate new bone growth and allows tumor to continue to grow

two types of neoplasias 

benign, malignant 

3 mechanisms of infectious agents associated with cancer development

interference with the immune system, destruction of tissue and inflammation, prolonged proliferation

how do promoting agents contribute to cancer development

they directly stimulate the cell cycle

name promoting agents naturally produced by the body 

estrogen and testosterone 

name a fusion oncoprotein generated by a chromosomal rearrangment and the cancer its associated with

BRC-ABL leukemia

name a cell type other than cancer cell that expresses high levels of telomerase

stem cell germ cell

Of the three cancers associated with genetic
predispositions: Retinoblastoma, Li-Fraumeni
syndrome and Xeroderma Pigmentosum, which
one displays a recessive cancer risk syndrome?

XP

Of the three cancers associated with genetic
predispositions: Retinoblastoma, Li-Fraumeni
syndrome and Xeroderma Pigmentosum, which
one displays a dominant cancer risk syndrome?

rb

Of the three cancers associated with genetic
predispositions: Retinoblastoma, Li-Fraumeni
syndrome and Xeroderma Pigmentosum, which
one displays a dominant cancer risk syndrome but recessive gene inheritance?

LF