Cancer the basics

Question 1

How are cancer cells defined?

Answer 1

1. reproduce in defiance of the normal restraints on cell division
2. invade and colonize territories normally reserved for other cells

Question 2

Where do cancers come from?

Answer 2

cancers usually arise from a single abormal cell

Monoclonal origin

Question 3

What is the evidence of a genetic basis for cancer?

Answer 3

• shared abnormality in their DNA
• Carcinogenesis is linked to mutagenesis
• high incidence of specific cancer types in certain families
• animals show predisposition to cancer which is passed from generation to generation

Question 4

Why are multiple mutations required to cause cancer?

Answer 4

increased incidence of cancer with age

delayed onset of cancer after exposure to carcinogen

cancer cells have multiple mutations in genes associated with cancer

animal models indicate that multiple mutations are required

Question 5

cancers develop in stages via what?

Question 6

T/F cancers arise from a single cell but develop in stages

Answer 6

true

Question 7

How does clonal evolution shape cancers?

Answer 7

• tumor progression involves successive rounds of mutation and selection
• some mutation gives an individual cell a growth advantage over surrounding cells

cancer progresses through different stages as mutations arise

Question 8

What are the 3 terms of cancer for its developing in clonal evolution?

Answer 8

• immortalization of indefinite growth
• transformation for independence of growth factors
• metastasis with invasion of growth at a distant site

Question 9

What are the general properties in converting cells to cancer cells?

Answer 9

loss of normal regulation of cell proliferation

tendency to avoid apoptosis

genetic instability

ability to escape from home tissue (invasiveness)

ability to survive and proliferate in foreign sites (metastasis)

Question 10

What are the genes critical to the development of cancer?

Answer 10

ongogenes (tumor promoter genes) - gain of function

tumor supressor genes - loss of function

Question 11

Define oncogenes wrt to cancer

Answer 11

genes that act in a dominant fashion to stimulate or sustain replication

mutation that activates them is a gain of function

Broad definition: any genes acting in a dominant fashion involved with cancer development in any way

Question 12

Define tumor suppressor genes wrt cancer

Answer 12

genes that act in a recessive manner resultingin either increased or sustained proliferation or decreased DNA repair

mutation is a loss of function

Question 13

What is an important difference in oncogenes and tumor suppressor genes?

Answer 13

loss of function requires mutations in both copies of the gene

Question 14

How was the first human oncogene identified?

Answer 14

oncogenic ras has a single point mutation and discovered using a viral method

Question 15

T/F oncogenes also have a normal cellular counterpart

Answer 15

true

Question 16

Describe why the development of cancer requires the cooperationof multiple cancer critical genes

Answer 16

with EITHER oncogene alone, sporadic tumors develop (even though all the cells are expressing the oncogene)

with BOTH oncogenes, tumors are still sporadic but are more and develop at an earlier age

Question 17

In what ways can proto-oncogenes become ongogenic?

Answer 17

• mutation in coding sequence
• gene amplification
• chromosome rearrangement

Question 18

How does mutation in coding sequence cause an oncogenic gene? What gene is associated?

Answer 18

hyperactive protein made in normal amounts

Ras gene

Question 19

How does an oncogene use gene amplification to promote cancer? What are the genes in this category?

Answer 19

normal protein greatly overproduced

Myc, Cyclin D, Erb-B1

Question 20

There are 2 ways in which chromosome rearrangement can promote oncogenic genes to become activated. Describe them and genes associated with each

Answer 20

• nearby regulatory DNA sequence causes normal protein to be overproduced

Myc, Cyclin D, Bcl-2, Src, Raf

• fusion to actively transcribe gene greatly overproduces fusion proteins or fusion protein is hyperactive

Abl

Question 21

Describe the tumor suppressor gene’s underactivity mutation (result and requirements)

Answer 21

1. normal cell gets a mutation and inactivates the tumor suppressor gene with no effect of mutation in one gene copy
2. second mutation inactivates second gene copy
3. functionally eliminate the tumor suppressor gene by stimulating cell proliferation

act in recessive manner needed 2 mutations in the gene sequence resulting in either increased or sustained proliferation or decreased DNA repair

Question 22

What is the evidence for the existence of tumor supproessor genes?

Answer 22

fusion of normal cells with tumor cells result in cells with a normal phenotype suggesting that there are tumor suppressors

Question 23

Describe the difference in the classification of the tumor suppressor genes

Answer 23

Gatekeepers: directly regulate cell growth

• neg regulators=> Rb, p53, APC, p19 ARf, p16 Ink4

Caretakers: involved in repairing DNA damage or maintaining genomic integrity

• ATM, Brca1, Brca2, Mlh1, Msh2

Question 24

Describe inherited retinoblastoma

Answer 24

occurs in childhood and arises in neural precursor cells in immature retina

usually multiple tumors in both eyes

increased susceptibility to other tumors

90% will develop a 2nd tumor w/in 30 years

defective Rb gene

Question 25

What type of oncogene is Rb? Why is that important?

Answer 25

loss of activity of tumor suppressor genes that promotes the formation of cancers both alleles must be activated

Question 26

Describe the FAP wrt cancer (gene associated, process)

Answer 26

familial polyposis coli hundreds to thousands of colon polyps develop by 20yrs polyps develop into colon cancer if not removed **inherited, inactivated, APC gene cause susceptibility to cancer**

Question 27

Describe the p53 gene wrt cancer

Answer 27

* transcription factor * induces cell cycle arrest at G1 in response to DNA damage * on chromosome 21 * induces apoptosis in response to excessive mitogenic stimulation or if the DNA damage cannot be repaired * induces genes required for DNA repair * inactivation of p53 leads to genome instability * E6 protein of HPV binds and inactivates p53

Question 28

What is the relationship of p53 and Li-Fraumeni?

Answer 28

Li-Fraumeni syndrome is due to defective p53 * inherited susceptibility to multiple cancers * by age 30\> 50% have tumors * age 50\> 90% have tumors

Question 29

What are the clinical characteristics of hereditary nonpolyposis colorectal cancer or Lynch syndrome?

Answer 29

hereditary predisposition to colon cancer WITHOUT an increase in incidence of polyps often present as colon cancer before age 50

Question 30

What are the mutations that cause Lynch syndrome or hereditary nonpolyposis colorectal cancer? What is the resulting karyotype and chromosome number?

Answer 30

mutaitons in 1 of 5 DNA repair genes (tumor suppressor genes) involved in DNA mismatch repair mutations in MLH1 and MSH2 together are responsible for 60-70% of HNPCC usually normal karyotype and chromosome number

Question 31

What genes are related to Familial breast cancer? Describe their type and how they are mutated to cause cancer

Answer 31

BRCA1 and BRCA2 mutations in BRCA1 and 2 genes =\> inherited predisposition to breast cancer BRCA1 and 2 are tumor suppressors both components of complex involved in homologous recombination repair

Question 32

Wrt proliferation, what are the similarites of cancer cells and stem cells?

Answer 32

tumor can acquire capacity for indefinite proliferation ability to give rise to new tissues **heterogenous combinations of cells with different phenotypic characteristics and different proliferative potentials**

Question 33

What evidence suggests that tumorigenic cancer cells undergo processes that are analogous to the self-renewal and differentiation of normal stem cells?

Answer 33

tumorigenic cancer cells must give rise to phenotypically diverse progency including cancer cells with indefinite proliferative potential along with cancer cells with limited or no proliferative potential

Question 34

Describe the 2 models of tumor heterogeneity

Answer 34

1. tumor cells are hetergenous but most can proliferate extensively and form new tumors 2. tumor cells are heterogeneous and only the cancer stem cell has the ability to proliferate extensively and form new tumors

Question 35

Are stem cells the target of transformation?

Answer 35

already actively proliferating few mutations may be required to establish the transormed phenotype restricted progenitors or differentiated cells would first need to acquire the self-renewal potential to have the opportunity then to accumulate mutations

Question 36

What will happen if the cancer arises in the progenitor cell?

Answer 36

cell must gain the prolonged self-renewal properties