Cancer Genetics

Question 1

What is a tumor defined as? How can tumors be classified?

Answer 1

Overgrowth of cell material; solid or dispersed, clonal (single mutation that begins); benign vs. malignant, with benign being milder and usually harmless, does not metastasize

Question 2

How does a tumor become malignant? What are the changes seen with malignancy?

Answer 2

Uncontrolled cell growth due to change in normal organization pattern of tissues or cells;
Karyotypic changes seen in most tumors, but also metastasis

Question 3

How does cancer arise?

Answer 3

Malignant tumor of potentially unlimited growth that expands locally by INVASION and systemically by METASTASIS

Question 4

Types of cancer? How do you classify a secondary tumor sometimes?

Answer 4

SARCOMA (mesenchymal tissues); CARCINOMA (epitheloid tissues); hematopoietic/lymphoid (leukemias with bone marrow and lymphomas with spleen and lymph nodes);
primary cancer in secondary location known by primary classification

Question 5

What are some environmental mutagens?

Answer 5

UV light; asbestos and cigarette smoke; plastics and dyes (red dye 3 banned)

Question 6

What are some hallmarks of cancer?

Answer 6

Mutation/loss of genes involved in cell control, environmental elements; mutations could be inherited or acquired; chromosome instability

Question 7

What is an oncogene and what is it carried by?

Answer 7

Dominantly acting gene dealing with unregulated cell growth and proliferation;
Viruses

Question 8

What are the five oncogenes?

Answer 8

HPV (cervical cancer); EBV, HHV-8, HTLV-1, HTLV-2

Question 9

Where are proto-oncogenes found? What can these genes give rise to?

Answer 9

Throughout the genome and mapped to nearly all chromosomes;

GFs, cell surface receptors, IC signal transduction, DNA binding proteins, regulation of cell cycle

Question 10

What can lead to activation of a proto-oncogene? What could this lead to in terms of changes? What process could this lead to? What type of mutation is it and how many are required?

Answer 10

Translocation, amp, point mutation; gene reg, transcription, protein product that can lead to alterations;
tumorigenesis;
gain of function; dominant (one mutation required)

Question 11

What is CML characterized by? What happens with the genes and the corresponding protein?

Answer 11

Translocation between chromosomes 9 and 22; fusion of proto-oncogene with second gene to give rise to chimeric protein (overproduction of tyrosine kinase)

Question 12

How can you treat CML, and what has this treatment helped reduce?

Answer 12

Bcr/abl specific tyrosine kinase inhibitor (target that one mutation with less side effects)

Question 13

What gives rise to acute promyelocytic leukemia? How can a translocation be detected?

Answer 13

15;17 translocation breaking PML gene on 15 and RARA gene on 17; gives chimeric protein product to give two fusion signals!!!

Question 14

What is clinically diagnostic of APL? How can you detect it? What is the term for normal signaling returning, and what happen if fusion pattern returns?

Answer 14

15;17 translocation; FISH; remission; relapse

Question 15

In contrast what does a tumor suppressor do? What type of mutations are required?

Answer 15

Loss or inactivation of gene allows cell to display alternate phenotype; need mutations of both alleles

Question 16

What are the two categories of tumor suppressor?

Answer 16

1. Gate keepers (suppress tumors by reg of cell cycle)

2. Caretakers (repair DNA damage and maintain genomic integrity, with accumulation of errors in cells)

Question 17

How are mutations of tumor suppressors expressed?

Answer 17

Solid tumors

Question 18

What does Rb1 function as?

Answer 18

Regulation of cell cycle (progression from G1 to S); eliminate important mitotic checkpoint resulting in uncontrolled growth

Question 19

What chromosome is Rb1 found on? What is an example of tumor suppressor mutations? When would the disease not occur?

Answer 19

13; retinoblastoma with tumor of retinoblasts (immature retinal cells); maturation to retinal cells (around five years of age)

Question 20

How can one be affected by retinoblastomas in terms of eyes affected? How can you treat it, and what’s the consequence? If one eye is affected, what’s the most likely cause? Two eyes affected? What is a possible secondary cancer?

Answer 20

Unilateral or bilateral; could treat with laser surgery, with a blind spot on the retina left over; sporadic vs. inherited;
osteosarcoma, or a bone tumor

Question 21

How could someone inherit something like retinoblastoma as opposed to acquiring it?

Answer 21

Inherit a mutation from e.g. mom and then somatically one could have a mutation leading to tumor if the mutation is in the RB1 locus within the same cell; in acquired, both mutations MUST OCCUR AT SOMATIC LEVEL AND MUTATIONS OCCUR IN SAME CELL

Question 22

How would a pattern of inheritance appear with retinoblastoma? However, what is characteristic of the mutations in terms of inheritance?

Answer 22

Dominant; recessive

Question 23

At what age would we see somatic mutations vs. familial mutations for something like breast cancer?

Answer 23

Usually older age of onset (50, 60, 70) vs. younger onset (20, 30) for something like breast cancer

Question 24

What is Li Fraumeni? What is it associated with?

Answer 24

Familial cancer syndrome and multiple neoplasia; inherited mutation of p53 (loss of checkpoint control of DNA damage)

Question 25

For breast cancer, how can one get it (2)? How much do these types of disease account for with breast cancer? What are the mutations, and in which genes would you see mutations?

Answer 25

Familial (5-10% of all breast cancers, being uni- or bilateral), sporadic accounts for 90-95% of all breast cancer cases;
Defects in HR and DNA repair;
2 genes: BRCA1 (near NF1 and p53) and BRCA2 (Rb1)

Question 26

For familial breast cancer, how much do BRCA1 and BRCA2 account for? What about breast cancer in general? Who is now at increased risk given these genes for breast cancer? What ethnic group?

Answer 26

80-90%; only 5-9% of all breast cancer;
increased risk of male breast cancer; increased risk in Ashkenazi Jew pop;
need to COUNSEL PATIENTS!!!

Question 27

What occurs with caretaker mutations and what genes are affected? What are examples of caretaker mutations?

Answer 27

Abnormal DNA builds up, genome unstable, and could affect proto-oncogenes or tumor suppressor genes;
Fanconi anemia, ataxia telangiectasia, breast cancer, HNPCC, bladder cancer

Question 28

What are characteristics of breakage syndromes?

Answer 28

Recessive inheritance, chromosome instability, defective DNA repair mechs; susceptibility to cancer

Question 29

How is chromosome instability demonstrated in breakage syndromes?

Answer 29

Unequal exchange with duplication of sequences on one chromatid and deletion on the other but mutations in DNA repair gene, triradials (replication error leading to fork), or excessive break of chromosomes

Question 30

What are examples of DNA repair defects in chromosome breakage syndromes?

Answer 30

Fanconi anemia, Bloom syndrome (ligase or helicase compromised), ataxia telangiectasia, xeroderma pigmentosum (excision repair) and Cockayne syndrome (excision repair cross complementation)

Question 31

What is the lifetime risk for males who inherit one mutation of HNPCC? What about women? What accounts for majority of HNPCC cases?

Answer 31

90% for men; 70% for women;

mutations in MSH2 and MLH1

Question 32

Trace out the path of normal mismatch repair. What happens with defects to this process?

Answer 32

Replication error –> delete mismatch –> repair by synthesis and ligation;
First step there, but failure to repair, and defect in DNA leads to additional mutation (one sequence okay, the other is not!!)

Question 33

What are present with microsatellites? What is it subject to? What can be diagnostic of HNPCC in a putative HNPCC tumor?

Answer 33

Repeats of 2, 3, or 4 nucleotides (e.g. AT or CGG);
replication error due to slippage as well as mutations in mismatch repair;
extra bands

Question 34

Can we directly test mismatch repair defects? What does microsatellite analysis of HNPCC suggest? How does HNPCC cause trouble?

Answer 34

No, we are not looking at the causative mutation, but the additional mutations that occur throughout genome; defect in mismatch repair;
malfunction of a normal cellular process that isn’t necessarily deleterious until errors accumulate!!

Question 35

Compare proto-oncogene and tumor supressor mutations:

Answer 35

Proto-oncogenes: dominant, acquired, chromosome translocation with amplications and point mutations, primary target is leukemias and lymphomas, gain or change of function;
Tumor suppressors: recessive, one mutant allele may be inherited, deletions with chromosome gain/loss and gene mutation, target solid tumors, loss of function, gate keeper or caretaker functions

Question 36

When is chromosome instability key with proto-oncogene and tumor suppressor mutations?

Answer 36

PO: chromosome translocation, amplification;
TS: deletions, chromosome loss;
also increased breakage and rearrangement in some diseases

Question 37

What mutations must be involved in cancer evolution? Where must these mutations occur? Is there an order to when they appear?

Answer 37

Both tumor suppressor (2 mutants) and proto-oncogenes (1 mutant); all in the SAME CELL; not necessarily an order so long as ALL THE MUTATIONS ARE PRESENT!!

Question 38

What occurs with clonality?

Answer 38

normal cell might have single mutation which proliferates and generates abnormal clone, and more chromosomal changes could make more clones (pg 333)

Question 39

What is karyotype evolution?

Answer 39

Change over time in karyotype due to acquisition of different mutations

Question 40

What tests are needed to detect molecular and chromosomal anomalies? What must you have?

Answer 40

Molecular diagnostics and/or cytogenetics (FISH, karyotype);

must have baseline

Question 41

What can chromosome rearrangements associated with leukemia help provide you?

Answer 41

If unique, provides specific diagnosis; if not, provides general diagnosis that an anomaly/disease is present

Question 42

What are Down syndrome patients at increased risk for?

Answer 42

Leukemia

Question 43

What is one tool that can help determine presence or absence of mutation? How can this homozygosity arise?

Answer 43

Loss of heterozygosity (apparent homozygosity);

example is a loss of one chromosome followed by possible duplication of the remaining chromosome (e.g. 17)

Question 44

What information could be used to determine the type of treatment utilized for certain mutations?

Answer 44

Direct correlation between particular chromosomal finding and course of disease sometimes!!

Question 45

If treatment only _________ the disease, what could occur with patient?

Answer 45

suppresses; relapse

Question 46

What can FISH be used to detect?

Answer 46

APL; mixed sex bone marrow transplant (to see if donor cells overwhelm host cells, or host cells still proliferate and kick out the donor cells)

Question 47

What anomaly can also be seen in some cancers that FISH can target?

Answer 47

Amplication such that tumor cells will have 2 green signals as a control but multiple red signals labeling the e.g. HER2-neu gene

Question 48

What detects most Bcr-abl rearrangements in terms of testing? What detects the rest?

Answer 48

Karyotype or FISH analysis; PCR

Question 49

What has sequencing enabled to do for detecting human cancers?

Answer 49

Development of unique signature panels; connect unique patterns to individual tumor identification

Question 50

For inherited cancers, where does the second mutation occur? What is risk correlated with?

Answer 50

Somatic level; risk correlated with number and degree of affected relatives, as well as inherited mutation which means could actually get the disease given a second mutation in the same cell!!!!