MCP 15&16

Question 0

Define benign

Answer 0

-milder, usually harmless, non-progressive disease does not metastasize

Question 1

Define tumor

Answer 1

• overgrowth of cell material, can be solid or dispersed
• clonality - all the cells typically originate from one mutated cell line
• can be benign or malignant

Question 2

describe clonal

Answer 2

• tumors generally start as a single cell with a mutation which proliferates to form a group of similarly abnormal cells

Question 3

Define malignancy

Answer 3

uncontrolled cell growth characterized by a change in the normal organization pattern of tissues or cells
-karyotypic changes, metastasis

Question 4

Define metastasis

Answer 4

when cells become invasive or migrate to another site. When they move they retain the original cell morphology. Therefore a tumor in the liver that was founded by breast cancer cells is still called breast cancer

Question 5

Define cancer

Answer 5

-malignant tumor or potentially unlimited growth that expands locally by invasion and systemically by metastasis -> overgrowth of cell material and clonal

Question 6

How is a primary cancer in a secondary location classified?

Answer 6

• classified by its primary location type

Question 7

Name some environmental factors that affect cancer incidence

Answer 7

UV light, asbestos, cigarette smoke, plastics dyes, red dye #3
- cancer most likley a combination of environmental and genetic factors

Question 8

Hallmarks of cancer

Answer 8

• mutations or loss of genes involved in cell control including growth/division, proliferation metabolism
• environmental elements may influence mutation
• mutations may be inherited or acquired
• chromosome instability (gain or loss of chromosomes)

Question 9

Oncogene

Answer 9

-a dominantly acting gene involved in unregulated cell growth and proliferation
-carried by viruses
-associated with disease in animals
H-ras-harvey rat sarcoma
sis-simian sarcoma virus
abl-abelson murine leukemia virus

Question 10

What are the oncogenes found in humans?

Answer 10

viral oncogenes in humans

• HPV -cervical cancer E6 and E7
• EBV- nasopharyngeal cancer, hodgkin and burkitt lymphoma
• HHV 8 - kaposi sarcoma
• HTLV -1- T cell leukemia
• HTLV-2 various leukemias
• mutation of other proto oncogenes

Question 11

Define proto-oncogenes

Answer 11

• critically important housekeeping genes that are present throughout the human genome and in their native state are not associated with diseases
• present throughout the genome and have been mapped to nearly all chromosomes

Question 12

List some of the functions of proto-oncogenes

Answer 12

• growth factors
• cell surface receptors
• intracellular signal transduction
• DNA binding proteins (transcription)
• regulation of cell cycle

Question 13

Describe what happens when proto-oncogenes go haywire

Answer 13

• mutation (translocation, amplification, point mutation) can result in “activation” of a proto-oncogene
• this may change gene regulation, gene transcription or a protein product generating alterations to cell growth, proliferation or differentiation
• can lead to tumorigenesis
• gain of function mutation
• dominant - only need one mutation

Question 14

what is clinically diagnostic of APL

Answer 14

• translocation of 15 and 17 is considered clinically diagnostic
• because of the need of hasty results FISH is generally performed first and then karyotype analysis

Question 15

Tumor suppressor

Answer 15

• genetic element whose loss or inactivation allows the cell to display an alternate phenotype leading to neoplastic growth
• oncogenetic potential when gene activity is lose
• true recessive

Question 16

Name and specify the two types of tumor suppressor gene types

Answer 16

gate keepers-> suppress tumors by regulating cell cycle or growth inhibition
caretakers - repair DNA damage and maintain genomic integrity -> effect is indirect via the accumulation of errors in the cells

Question 17

List some normal functions of tumor suppressor genes

Answer 17

• cell to cell interactions
• regulation of growth inhibitory substances
• cell differentiation
• chromosome repair
• cell proliferation

Question 18

What type of cancers do tumor suppressor genes have the biggest influence over?

Answer 18

solid tumors!

- difficult to culture

Question 19

Name a classic gate keeper disease

Answer 19

Rb 1 functions in regulation of cell cycle

• controls progression from g1 to s
• loss of function eliminates an important mitotic checkpoint resulting in uncontrolled growth

Question 20

Retinoblastoma

Answer 20

An example of a tumor suppressor is seen in this disease which is a tumor of the retinoblastoma (immature cells of the retina). Once retinoblastoma mature to retinal cells the target tissue of this disease is gone and the disease does not occur after age of 5. 
- 1/20,000
- prenatal to age 5 
-unilateral usually sporadic 
- bilateral usually inherited
- secondary cancer Osteosarcoma 
Severe cases require enucleation
Some may be treated by laser surgery

Question 21

Knudson’s two hit hypothesis

Answer 21

Two mutations in same cell
Sporadic usually unilateral
Inherited usually bilateral
Appearance of dominance but truly recessive

Question 22

Earlier age of cancer onset

Answer 22

If a person inherits one mutation his/her disease will occur early in life (birth to 30) since it generally will not take a long time for the second mutation to occur and initiate carcinogensis

Question 23

Later age of onset of cancer

Answer 23

If not mutation is inherited two mutation must occur sporadically to initiate the abnormal clone. This will require more time and these cancers typically occur in the later decades of life

Question 24

Li fraumeni

Answer 24

- familial cancer syndrome - multiple neoplasia - increased risk of cancer 50% at age 30, 90% at age 70 - inherited mutation of p53 ( lose checkpoint of DNA damage)

Question 25

Where are BRCA 1 and BRCA 2 located ?

Answer 25

BRCA 1 -> chromosome 17 (near NF1 and p53) | BRCA20 -> chromosome 13 (near rb1)

Question 26

Why is the mortality higher in males with breast cancer?

Answer 26

Higher bc people don't think it can happen to men and it takes longer for them to seek care

Question 27

BRCA1 and BRCA2

Answer 27

80-90% of familial breast cancer 5-9% of all breast cancer Multiple mutations Increased risk for male breast cancer as well Increased risk in Ashkenazi Jewish population Counseling patients is critical

Question 28

Caretaker mutations

Answer 28

Inability to repair DNA defects mutations - accumulations of abnormal DNA genes -Increased risk of genome instability -May lead to mutation of proto-oncogene tumor suppressor genes Inherited or acquired

Question 29

List some examples of breakage syndromes

Answer 29

- fanconi anemia - Bloom syndrome - ataxia telanglectasia - xeroderma pigmentosum - cockayne syndrome

Question 30

What four features do breakage syndromes share?

Answer 30

1. Recessive inheritance 2. Chromosome instability 3. Defective DNA repair machinery 4. Susceptibility to cancer

Question 31

Triadials

Answer 31

Replication has resulted in a Y shaped or fork structure

Question 32

Hereditary nonpolyposis colon

Answer 32

2-4% of hereditary colon cancer 90% lifetime risk or males who inherit one mutation 70% lifetime risk for females who inherit one mutation -40% risk of endometrial cancer -10-20% risk of urinary tract cancer -10-20% risk of ovarian cancer

Question 33

Mismatch repair

Answer 33

If an error occurs during replication it is detected by checking enzyme excised along with adjacent bases and missing portion is filled in correctly and ligated back to existing DNA

Question 34

What happens when mismatch repair goes wrong?

Answer 34

Two cell lines, one with the appropriate sequence and one with the incorrect, mutated sequence

Question 35

Microsatellites

Answer 35

Repeats of 2, 3, or 4 nucleotides -> highly polymorphic in population and can be in DNA analysis because subject to replication error use to slippages Also mutations in mismatch pairs can alter total number of repeats For example change in pattern of repeats can be indicative of mutation used for HNPCC diagnosis

Question 36

Cancer evolution

Answer 36

Progression from normal to cancer cells requires a combination of environmental and genetic effects Many different mutations occur but the key principle is that these mutations must occur in the same cell

Question 37

Define clonality

Answer 37

A normal cell may have a single mutation which proliferates and generates an abnormal clone this is an acquired change in a limited number of cells. Further chromosomal changes may modify the karyotype and produce additional clones - karyotype analysis can be used to monitor the presence and evolution of clones

Question 38

Define karyotype analysis

Answer 38

Change over time in the karyotype due to acquisition different mutations. Generally increasing complexity and number of chromosome abnormalities are associated I with poorer prognosis.it is possible to use chromosome abnormalities to follow patient from diagnosis to remission and relapse.

Question 39

Define constitutional findings

Answer 39

Original DNA and chromosome complement that is the foundation for the genetic constitution in all cells of the body Originate in zygote

Question 40

Acquired anomalies

Answer 40

A change which has occurred in the constitutional DNA or karyotype - usually present in a single cell line or clone

Question 41

Define loss of heterozygosity

Answer 41

Apparent homozygosity or hemizygosity in a tissue which demonstrates heterozygosity constitutionally Demonstrates the importance of having a baseline

Question 42

Prognosis

Answer 42

- in some instances there is a direct correlation between particular chromosomal finding and the course of the disease - knowing that information may aid in determine the type of treatment utilized - a more resistant disease may be treated more aggressively