Rr 08 Neoplasms Part 3

Front 1

Describe carcinogenesis

Back 1

Cancer is a multistep process involving gene mutations, telomerase activation, angiogenesis, invasion, and metastasis

Front 2

Describe the types of gene mutations involved in carcinogenesis

Back 2

1. Point mutations are the most common type of mutation
2. Balanced translocations
3. Other mutations
-Deletion, gene amplification (multiple copies of a gene), overexpression (increase in baseline gene activity)

Front 3

Describe proto-oncogenes

Back 3

1. Involves in normal growth and repair
2. Functions of proto-oncogene protein products
-Growth factors, growth factor receptors, signal transducer, nuclear transcribers
3. Mutations cause sustained activity of the genes

Front 4

Describe tumor suppressor genes (anti-oncogenes)

Back 4

1. Protect against unregulated cell growth
2. Control G1 to S phase of the cell cycle and nuclear transcription
3. Mutations cause unregulated cell proliferation

Front 5

Describe antiapoptosis genes

Back 5

-BCL2 family of genes
1. Protein products prevent cytochrome C from leaving mitochondria
-Cytochrome c in the cytosol activates caspases initiating apoptosis
2. Mutation causes increased gene activity (eg, overexpression), which prevents apoptosis; eg B-cell follicular lymphoma
a. BCL2 gene family (chromosome 18) produces gene products that prevent mitochondrial leakage of cytochrome c (signal for apoptosis)
b. Translocation t(14;18) causes overexpression of the BCL2 protein product.
-Prevents apoptosis of B lymphocytes causing B-cell follicular lymphoma

Front 6

Describe the apoptosis genes

Back 6

1. Regulate programmed cell gene
2. Example: BAX apoptosis gene
a. Activated by a TP53 suppressor gene product if DNA damage is excessive
b. BAX protein product inactivates the BCL2 antiapoptosis gene
c. Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative, which prevents apoptosis

Front 7

Describe the causes of cancer

Back 7

1. External factors
-Tobacco, alcohol, chemicals, radiation, pathogens
2. Internal factors
-Hormones, immune conditions, inherited mutations

Front 8

Describe the function, mutation, and cancer associated with the proto-oncogene ABL

Back 8

Function: Nonreceptor tyrosine kinase activity
Mutation: Translocation t(9;22)
Cancer: Chronic myelogenous leukemia (chromosome 22 is Philadelphia chromosome)

Front 9

Describe the function, mutation, and cancer associated with the proto-oncogene HER (ERBB2)

Back 9

Function: Receptor synthesis
Mutation: Amplification
Cancer: Breast carcinoma (marker of aggressiveness)

Front 10

Describe the function, mutation, and cancer associated with the proto-oncogene MYC

Back 10

Function: Nuclear transcription
Mutation: Translocation t(8;14)
Cancer: Burkitt’s Lymphoma

Front 11

Describe the function, mutation, and cancer associated with the proto-oncogene N-MYC

Back 11

Function: Nuclear transcription
Mutation: Amplification
Cancer: Neuroblastoma

Front 12

Describe the function, mutation, and cancer associated with the proto-oncogene RAS

Back 12

Function: Guanosine triphosphate signal transduction
Mutation: Point mutation
Cancer: Leukemia; lung, colon, pancreatic carcinomas

Front 13

Describe the function, mutation, and cancer associated with the proto-oncogene RET

Back 13

Function: Receptor synthesis
Mutation: Point mutation
Cancer: Multiple endocrine neoplasia IIa/IIb syndromes

Front 14

Describe the function, mutation, and cancer associated with the proto-oncogene SIS

Back 14

Function: Growth factor synthesis
Mutation: Overexpression
Cancer: Osteogenic sarcoma, astrocytoma

Front 15

Describe the function and associated cancers associated with the tumor suppressor gene APC

Back 15

Function: Prevents nuclear transcription (degrade catenin, an activator of nuclear transcription)
Associated cancers: Familial polyposis (colorectal carcinoma)

Front 16

Describe the function and associated cancers associated with the tumor suppressor gene BRCA1/BRCA2

Back 16

Function: Regulates DNA repair
Associated cancers: Breast, ovary, prostate carcinomas

Front 17

Describe the function and associated cancers associated with the tumor suppressor gene RB (retinoblastoma)

Back 17

Function: inhibits G1 to S phase
Associated cancers: Retinoblastoma, osteogenic sarcoma, breast carcinoma

Front 18

Describe the function and associated cancers associated with the tumor suppressor gene TGF-beta

Back 18

Function: Inhibits G1 to S phase
Associated cancers: Pancreatic and colorectal carcinomas

Front 19

Describe the function and associated cancers associated with the tumor suppressor gene TP53

Back 19

Function: (1)Inhibits G1 to S phase, (2) Repairs DNA, activates BAX gene (initiates apoptosis)
Associated cancers: (1) Lung, colon, breast carcinomas (2) Li-Fraumeni syndrome: breast carcinoma, brain tumors, leukemia, sarcomas

Front 20

Describe the function and associated cancers associated with the tumor suppressor gene VHL (von Hippel-Lindau)

Back 20

Function: Regulates nuclear transcription
Associated cancers: Von Hippel-Lindau syndrome: cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma (bilateral), pheochromocytoma (bilateral)

Front 21

Describe the function and associated cancers associated with the tumor suppressor gene WT1

Back 21

Function: Regulates nuclear transcription
Associated cancers: Wilm’s tumor

Front 22

Describe DNA repair genes

Back 22

1. Examples of DNA repair
a. Mismatch repair genes produce proteins that correct errors in nucleotide pairing
b. Nucleotide excision repair pathway excises pyrimidine dimmers in UV light-damaged skin
2. Effect of mutations involving DNA repair genes
-Allows cells with nonlethal damage to proliferate, which increases the risk for cancer

Front 23

What is the most common group of carcinogens in the US?

Back 23

Polycyclic hydrocarbons in tobacco smoke

Front 24

Describe the mechanisms for chemical carcinogens

Back 24

1. Direct-acting carcinogens
-Contain electro-deficient atoms that react with electron-rich atoms in DNA (eg alkylating agents)
2. Indirect-acting carcinogens
-Activated by the liver cytochrome P450 system (eg, polycyclic hydrocarbon)

Front 25

Describe the sequence of chemical carcinogenesis

Back 25

1. Initiation
-Irreversible mutation
2. Promotion
-Promoters (eg estrogen) stimulate mutated cells to enter the cell cycle
3. Progression
a. Development of tumor heterogeneity
b. Examples- production of cells that invade or metastasize

Front 26

Describe the associated cancers with the carcinogen aflatoxin (from Aspergillus)

Back 26

Hepatocellular carcinoma in association with hepatitis B virus

Front 27

Describe the associated cancers with the carcinogen alcohol

Back 27

Squamous cell carcinoma of oropharynx and upper/middle esophagus; pancreatic and hepatocellular carcinomas

Front 28

Describe the associated cancers with the carcinogen alkylating agents

Back 28

Malignant lymphoma

Front 29

Describe the associated cancers with the carcinogen arsenic

Back 29

Squamous cell carcinoma of skin, lung cancer, liver angiosarcoma

Front 30

Describe the associated cancers with the carcinogen asbestos

Back 30

Bronchogenic carcinoma, pleural mesothelioma

Front 31

Describe the associated cancers with the carcinogen benzene

Back 31

Acute leukemia

Front 32

Describe the associated cancers with the carcinogen beryllium

Back 32

Bronchogenic carcinoma

Front 33

Describe the associated cancers with the carcinogen chromium

Back 33

Bronchogenic carcinoma

Front 34

Describe the associated cancers with the carcinogen cyclophosphamide

Back 34

Transitional cell carcinoma of urinary bladder

Front 35

Describe the associated cancers with the carcinogen diethylstilbestrol

Back 35

Clear cell carcinoma of vagina/cervix

Front 36

Describe the associated cancers with the carcinogen beta-naphthylamine (aniline dyes)

Back 36

Transitional cell carcinoma of urinary bladder

Front 37

Describe the associated cancers with the carcinogen nickel

Back 37

Bronchogenic carcinoma

Front 38

Describe the associated cancers with the carcinogen oral contraceptives

Back 38

Breast, cervical carcinomas

Front 39

Describe the associated cancers with the carcinogen polycyclic hydrocarbons

Back 39

1. Squamous cell carcinoma: oral cavity, midesophagus, larynx, lung
2. Adenocarcinoma: Distal esophagus, pancreas
3. Transitional cell carcinoma: Urinary bladder, renal pelvis

Front 40

Describe the associated cancers with the carcinogen polyvinyl chloride

Back 40

Liver angiosarcoma

Front 41

Describe the associated cancers with the carcinogen silica

Back 41

Bronchogenic carcinoma

Front 42

Describe the mechanism and associated cancer from the RNA virus HCV

Back 42

Mechanism: Produces postnecrotic cirrhosis
Associated cancer; Hepatocellular carcinoma

Front 43

Describe the mechanism and associated cancer from the RNA virus HTLV-1

Back 43

Mechanism: Activates TAX gene, stimulates polyclonal T-cell proliferation, inhibits TP53 suppressor gene
Associated Cancer: T-cell leukemia and lymphoma

Front 44

Describe the mechanism and associated cancer from the DNA virus EBV

Back 44

Mechanism: Promotes polyclonal B-cell proliferation, which increases risk for t(8;14) translocation
Associated cancer: Burkitt’s lymphoma, CNS lymphoma in AIDS, mixed cellularity Hodgkin’s lymphoma, nasopharyngeal carcinoma

Front 45

Describe the mechanism and associated cancer from the DNA virus HBV

Back 45

Mechanism: Activates proto-oncogenes, inactivates TP53 suppressor gene
Associated cacner: Hepatocellular

Front 46

Describe the mechanism and associated cancer from the DNA virus HHV-8

Back 46

Mechanism: Acts via cytokines released from HIV and HSV
Associated cancers: Kaposi’s sarcoma in AIDS

Front 47

Describe the mechanism and associated cancer from the DNA virus HPV types 16 and 18

Back 47

Mechanism
Type 16 (~50% of cancers): E6 gene product inhibits TP53 suppressor gene
Type 18 (~10% of cancers): E7 gene product inhibits RB suppressor gene
Associated Cancer:
Squamous cell carcinoma of vulva, vagina, cervix, anus (associated with anal intercourse), larynx, oropharynx

Front 48

Describe microbes associated with cancer

Back 48

1. Viruses
2. Bacteria
-Examples: stomach cancer and low-grade malignant lymphoma due to H. pylori
3. Parasites
a. Schistosoma hematobium
-Squamous cell carcinoma
b. Clonorchis sinesis and Opisthorchis viverrini

Front 49

Describe ionizing radiation-induced cancers

Back 49

1. Mechanism
-Hydroxyl free radical injury to DNA
2. Examples
a. Acute myelogenous or chronic myelogenous leukemia
-Increased risk of leukemia in radiologists and individuals exposed to radiation in nuclear reactors
b. Papillary thyroid carcinoma
c. Lung, breast, and bone cancers
d. Liver angiosarcoma
-Due to radioactive thorium dioxide used to visualize the arterial tree

Front 50

Describe UV light-induced cancers

Back 50

1. Mechanism
-Formation of pyrimidine dimers, which distort DNA
2. Basal cell carcinoma, squamous cell carcinoma, malignant melanoma