Cancer

Question 1

What are the steps involved in cancer transformation?

Answer 1

1. 1st mutation acquired–selective growth of that cell line
2. Additional mutations acquired, each providing a selective advantage
3. expansion produces an increasingly unregulated/aggressive clone line
4. Tumor

Question 2

3 normal cell functions disrupted in a malignant transformation:

Answer 2

Repair
Growth
Cell-to-cell interactions

Question 3

6 mechanisms involved in malignant transform:

Answer 3

Mutation
Structural rearrangement
Copy number changes
Epigenetics
miRNA
telomerase

Question 4

Explain the typical multi-step process of cancer development

Answer 4

Normal epithelium -> loss of TS drives hyperprolif
Activation of oncogene -> early adenoma
Continual loss of tumor suppressor genes -> cancer

*oncogene activation drives loss of suppressor

Question 5

What changes accompany clonal expansion?

Answer 5

Genetic heterogeneity
(from one starting cell, heterogeneous tumor cell variants)

Question 6

What is characteristically unstable in tumors?

Answer 6

Heterogenous genomic instability

Question 7

Oncogenes are growth (promoting/restricting)

Answer 7

Promoting

Question 8

TS genes are growth (promoting/restricting)

Answer 8

Restricting

Question 9

Oncogenes are associated with (gain/loss) of function mutations

Answer 9

Gain

Question 10

TS genes are associated with (gain/loss) of function

Answer 10

Loss

Question 11

What cancer is caused by RB1?

Answer 11

Retinoblastoma

Question 12

What cancer is associated with MLH1, MLH2 and MLH6? What is dysfunctional if mutated?

Answer 12

Lynch syndrome

DNA repair

Question 13

What is the relationship between TS genes and cancer?

Answer 13

Loss or inactivation of both TS alleles -> cancer

Question 14

60% of retinoblastoma results from _______ mutations, in which both alleles are acquired

Answer 14

Sporadic

Question 15

40% of retinoblastoma results from _______ mutations, in which one allele is acquired

Answer 15

Hereditary

Question 16

Associated with constitutional heterogeneity in a tumor suppressor gene line

Answer 16

Hereditary mutations

Question 17

T/F: Once a tumor is formed, mutation accumulation is no longer necessary.

Answer 17

F–tumor formation drives additional mutations

Question 18

How do hereditary cancers caused by TS genes segregate?

Answer 18

Autosomal dominant with reduced penetrance

Question 19

At the level of a patient with a hereditary TS-associated cancer, the phenotype is:

Answer 19

Dominant

Question 20

At the level of a tumor in a hereditary TS-associated cancer, the phenotype is:

Answer 20

Recessive

Question 21

Tumor cells are (hetero/homo)zygous mutants

Answer 21

Homozygous (they acquire a second mutation)

Question 22

What occurs in the “2nd hit”?

Answer 22

Loss of the normal allele

Question 23

Most common mechanisms of second hit (in terms of DNA segment loss)?

Answer 23

Microdeletion
Mitosis nondisjunction
Mitotic recombination

Question 24

What are 3 ways that function of the normal allele is lost in 2nd hit?

Answer 24

1. loss of heterozygosity
2. Point mutations
3. Epigenetic silencing

Question 25

3 ways that oncogenes are activated?

Answer 25

``` point mutations (example: RAS) acquired reciprocal translocations gene amplification (100/s of copies in cell) ```

Question 26

BCR-ABL fusion is associated with what disorder? How does this occur?

Answer 26

CML | Activates oncogene via reciprocal translation

Question 27

How does imatinib treat BCR-ABL fusion?

Answer 27

Targets actual fusion protein

Question 28

Explain gene amplification.

Answer 28

The tumor cell has hundreds of copies of proto-oncogenes, which confers a selective advantage

Question 29

2 types of gene amplification

Answer 29

1. HSR (homogeneously staining regions) visiable as an extra non-banded region 2. DM (double minutes) extrachromosomal, circular DNA lacking centromeres and telomeres

Question 30

This type of gene amplification is associated with random segregation

Answer 30

DM

Question 31

T/F: Extreme abnormal copy number variation is often present in tumors, but may also be constitutional

Answer 31

F: Never constitutional

Question 32

Type of amplification common in breast cancers?

Answer 32

HER2 (an EGFR)

Question 33

Chromosomal aberrations in cancer may lead to:

Answer 33

Aneuploidy (full or partial) Apparently intact chromosomes (but with abnormalities)

Question 34

What is involved in the multistep process of malignant transformation?

Answer 34

Multiple acquired (somatic) mutations Clonal expansion of the altered cell lines