Cancer Genetics II - RM (Lecture 16)

Question 1

What are triradials?

Answer 1

replication error that resulted in Y-shaped/forked chromosome instead of normal linear chromosome

Question 2

Why are chromosomes unstable in chromsomal instability diseases?

Answer 2

patients lack the fundamental process of DNA repair

failure to repair genes–>instability–>increased risk for cancer

Question 3

What type of genes are HNPCC1, HNPCC2, HNPCC5? Is it a tumor suppressor or protooncogene expression of disease?

Answer 3

DNA mismatch repair genes

tumor suppressor

Question 4

Why is hereditary nonpolyposis colon cancer inheritable?

Answer 4

because it is caused by mutation of 2 genes and you can pass along the one mutation, which increases risk of offspring getting cancer

Question 5

What type of gene is HNPCC6? (tumor suppressor or protoncogene)

Answer 5

protooncogene, it is a growth factor receptor involved in cell growth

Question 6

How do defects in mismatch repair lead to cancer?

Answer 6

if mismatch occurs and isn’t repaired, the DNA will replicate to produce one normal daughter cell and one with mutated sequence that can proliferate and evolve into abnormal cell line

Question 7

What are microsatellites?

Answer 7

repeats of 2, 3 or 4 nucleotides present throughout genome that are highly polymorphic in population

Question 8

Why do you screen for mismatch repair in microsatellites?

Answer 8

microsatellites are particularly sensitive to defects in DNA repair and subject to replication error due to slippage that will alter the total numbers of repeats (usually amplify)
-easier than screening each mismatch repair gene

Question 9

Is screening microsatellites a direct or indirect test?

Answer 9

indirect test–looks for the effects of the mutation in mismatch repair gene rather than the defect directly

Question 10

Does protooncogene or tumor suppressor gene mutation lead to leukemia/lymphoma?

Answer 10

protooncogene

Question 11

Does protooncogene or tumor suppressor gene mutation lead to solid tumors?

Answer 11

tumor suppressor gene

Question 12

What is an example of a gatekeeper tumor suppressor gene? of a caretaker one?

Answer 12

gatekeeper–Retinoblastoma (Rb)

caretaker-mismatch repair/DNA repair

Question 13

Why is chromosome instability a hallmark of cancer?

Answer 13

it leads to breakage, chromosome rearrangements, and gain/loss of whole chromosomes

Question 14

What is the requirement for the accumulation of mutations leading to cancer?

Answer 14

they all must occur in the same single cell, but do not need to occur in sequential order

Question 15

What type of gene is APC?

Answer 15

gate keeper (tumor suppressor gene)

Question 16

What is clonality?

Answer 16

normal cell may have a single mutation which proliferates and generates an abnormal clone, which is an acquired change for limited number of cells
-further chromosomal damages may modify karyotype and produce additional clones

Question 17

What is karyotype evolution?

Answer 17

change over time in the karyotype due to acquistion of different mutations

Question 18

What does increasing complexity and number of chromosomal abnormalites say about the prognosis for the patient?

Answer 18

poorer prognosis

Question 19

What is remission? how can you test for it?

Answer 19

suppression of abnormal cell line below detection, don’t see the chromomsomal abnormalities upon karyotype analysis and don’t see the disease phenotype

Question 20

What is it called when disease resurfaces, possibly with new abnormalities in the cell line?

Answer 20

relapse

Question 21

Why must you have a baseline for clinical testing for cancer?

Answer 21

• need to know individual’s genetic condition at diagnosis and how it compares to normal genome
• need to be able to see any evolution of the mutations

Question 22

What are constitutional findings?

Answer 22

original DNA and chromosome complement that is the foundation for genetic constitution in all cells of body (originated in zygote)

Question 23

What are examples of loss of genetic material?

Answer 23

deletion, monosomy

Question 24

What are examples of gain of genetic material?

Answer 24

duplication, trisomy, gene amplification

Question 25

What is relocation of genetic material?

Answer 25

translocation

Question 26

Is the t(15;17) rearrangement unique for a disease? if so, which?

Answer 26

yes, for APL

Question 27

is the t(9;22) rearrangement unique for a disease? If so, which?

Answer 27

No, could be for AML or CML, need to look at morphology to determine diagnosis

Question 28

Why do Down Syndrome patients have increased risk for leukemia?

Answer 28

RUNX1 on chromosome 21 associated with leukemia and having three copies increases risk

Question 29

What is loss of heterzygosity?

Answer 29

apparent homozygosity or hemizygosity in a tissue which demonstrates heterozygosity constitutionally

Question 30

How do you test for loss of heterozygosity?

Answer 30

use markers known to be heterozygous in unaffected tissues and evaluate state in tumor DNA by number of markers present
–>if test reveals homozygosity it’s probably due to disease and is actually LOH

Question 31

Does LOH mean there is only a single allele present?

Answer 31

No, tumors may have multiple copies of the target chromosome but only a single band on DNA analysis due to loss of original heterozygosity and then duplication of the remaining allele to give multiple copies of same chromosome

Question 32

How has FISH increased the statistical significance of analysis of frequency of the disease?

Answer 32

can quickly identify chromosomal abnormalities with probes, allows more cells to be scored, and increases level of significance of study

Question 33

What is the pitfall of FISH?

Answer 33

only those abnormalities being specifically tested for will be assessed so you could miss another anomaly

Question 34

Why is FISH useful in mixed sex bone marrow transplants?

Answer 34

can easily score cells for XX or XY to determine relative proportions of different populations

Question 35

How is the success of a bone marrow transplant measured?

Answer 35

measure the number of cells from recipient and donor populating the bone marrow–>donor population should engraft and become dominant cell line and recipient’s cells should die off

Question 36

How are HER-2 amplifications in breast cancer quantified?

Answer 36

FISH detects HER-2 cells with red probe and control locus with green
normal cells– 2 green, 2 red
tumor cells–2 green, multiple reds–>amplified gene

Question 37

What types of breast cancer will respond to herceptin?

Answer 37

HER-2 positive

Question 38

How is BCR-ABL rearrangment detected?

Answer 38

95% detected by karyotype or FISH, other 5% can be picked up by PCR

Question 39

What do expression arrays demonstrate? What does red, green and black mean?

Answer 39

the expression of certain genes and proteins specific to particular cancers
red–increased expression
green–decreased expression
black–median expression

Question 40

How do expression arrays affect diagnosis?

Answer 40

run standard “signature” panels for each tumor that is based on sequencing fingerprint of genes expressed in it against a patient sample

Question 41

What % does a carrier patient have of passing on a mutation for inherited cancer?

Answer 41

50%

Question 42

Where does the second mutation in inherited cancer occur?

Answer 42

on the somatic level

Question 43

What is the risk of inheriting cancer correlated to?

Answer 43

number and degree of affected relatives