MCM 2-14 & 2-15 Cancer Genetics I & II

Question 1

oncogones

Answer 1

dominantly acting genes involved in unregulated cell growth and proliferation.

-appear in humans via viral transduction or activation of proto-oncogenes

Question 2

describe proto-oncogones

Answer 2

important housekeeping genes involved in cell proliferation and development

encode growth factors, cell surface receptors, and cell cycle regulators

precise effect on cell depends on what proto-oncogene is mutated. in general, the mutation of a proto-oncogene is a gain of function mutation that leads to tumorigenesis.

mutations act dominantly, only one mutated allele is neeeded for negative effects to manifest

Question 3

most proto oncogene mutations result in

Answer 3

leukemias and lymphomas

Question 4

describe tumor suppressors

Answer 4

genetic elements whose normal function including mediating cell-cell interactions, regulation of growth inhibitory substances, and cell proliferation.

the loss of inactivation of these allows the cell to display an alternate phenotype leading to neoplastic growth

mutation acts recessively, two mutated alleles are needed.

Question 5

describe the inheritance pattern of oncogene mutations, tumor suppressor mutations, and DNA repair mutations

Answer 5

oncogone mutations - dominantly acting, only one mutated allele is enough to cause illness

tumor suppressors - recessive. two mutated alleles are needed for negative effects to manifest. Somatic mutations tend to have onset later in life as it takes time to acquire the mutations in the single cell. Inherited (familiar) mutations tend to have earlier onset

DNA repair genes - recessive mode of inheritance, can be inherited or acquired

Question 6

DNA repair gene defects

Answer 6

defects in these genes leads to an inabiltiy to repair DNA defects/mutations, leading to increased genome instability, highetining the risk of widespread mutations that may effect tumor suppressors or proto-oncogenes

Question 7

DNA repair gene defects can lead to what diseases?

Answer 7

lead to genome instability which causes chromosome breakage syndromes

xeroderma pigmentosum and HNPCC

Question 8

Chronic Myelogenous Leukemia (CML)

Answer 8

common leukemia caused by oncogene activation

• first cancer associated with cytogenic marker (trnslatocation of chromsosomes 9 and 22)
• longer 9 and altered 22 (philadelphia chromosome)

discovery allows physicians to develope a drug that attacks the specific mutant protein that causes disease

Question 9

Retinoblastoma

Answer 9

loss of function mutation in the RB1 tumor supressor, leads to loss of mitotic checkpoint between G1 and S leading to uncontrolled growth.

common RB1 mutation is deletion, generally the first abnormality looked for when screening for Rb1 mutations

unilateral (one tumor) disease is sporatic (random), while bilateral (multiple tumors in one or both eyes) is inherited.

autosomal recessive inheritance, but which high rate of sporatic mutation of second allele in those with inherited mutant allele.

Question 10

Li-Fraumeni Syndrome

Answer 10

familiar cancer syndrome (inherited)

associated with increased cancer risk of various phenotypes (depending on environmental factors) due to inherited mutation of p53

Question 11

breast cancer

Answer 11

familiar OR sporatic, due to mutations in homo recombination or DNA repair defects

BRCA1,2 are two genes that are associated with DNA repair defects and occur in 90% of familiar cases.

because familiar cases are less than 10%, BRCA 1 and 2 account for only 5-9% of breast cancers. In most cases the sporatic mutations are predominant, there are multiple mutations involved.

Question 12

describe clonal expansion

Answer 12

cancer tumors tend to be clonal. cell metabolism/proliferation triggers the cell into a different pathway. these mutations are often deleterious, but some will survive and form a new cell line.

Question 13

how are cancers named?

Answer 13

by primary tissue of organ

a primary cancer which has metastasized to a secondary area is known by the primary classification (aka, breast cancer that spread to the liver). The cancer cells in the liver will be breast cancer cells.

Question 14

constitutional vs acquired anomalies

Answer 14

constitutional findings - present in zygote, basic genetic constitution. Anything that happens to this DNA after this point are acquired changes

Acquired changes- occurs to DNA afterwards, this is normal, and often get cleared up by maintenance enzymes in the cells. But when not cleared, can sometimes lead to cancer

Question 15

driver vs passenger

Answer 15

driver - the mutation immediately involved with cancer or changes in cell leading to cancer

passenger - mutations which have not been seen in direct correlation, may be random

a cancerous karyotype which is badly mutated, can be difficult to determine which mutation lead to the cancer, and which is a side effect of the genomic instability cause by the primary mutation

Question 16

Primary driver genes are classified into

Answer 16

mutations of genes involved in cell death or proliferation

mutations of genes involved in genomic integrity or expression

Point - there are many targets in the cell, many points where errors can occur and cause cancer.

Question 17

proteo-oncogenes can be subject to many different types of mutations. What effects does this have?

Answer 17

this leads to many different possibly changes in the product that is formed.

regulatory mutation may cause excess protein to be created

while translocation mutations may create a new novel protein

Question 18

normal vs abnormal findings of FISH in CML

Answer 18

normal - two red and two green, showing we have two distinct copies of chromosome 17 and 15

abnormal - 1 green, 1 red, and two yellow as a result of the mutual translocation between the two chromosomes

Question 19

using microsattelites to find repeats suggesting a defect in mismatch repair what what type of testing?

Answer 19

indirect testing, we are not looking for mutation itself but looking for the effects of the mutation

Question 20

Proto oncogene summary

Answer 20

dominantly acting, acquired, chromosome translocation, amplification, point mutation
primary target - leukemias/lymphomas

gain or change of function

Question 21

tumor supressor summary

Answer 21

recessive - 1 mutation is enough
deletions, chromosomal gain/loss, gene mutation
-primary target -solid tumors
-loss of function mutation

Question 22

describe cancer evolution

Answer 22

series of mutations that occur, generally in a stepwise fashion, leading to cancer and possibly metastasis. Each step is a mutation in a particular “Gatekeeper” gene, and must have all of these mutations in a single cell.

we are most concerned about the first step or “Trigger step” which often causes the cascade. This trigger step is already present in those who have inherited the mutation on one allele.

Question 23

how do we determine if a patient is getting better or worse

Answer 23

we must take a baseline at the time of diagnosis

Question 24

people with downs syndrome are more susceptible to leukemia. Why or why not?

Answer 24

The trisomy 21 constitutional karyotype that they are born with.

Question 25

how do we determine if a bone marrow transplant is succssful

Answer 25

should do mixed sex
example) female donor, male recipient

after clearing out the patients cells with radiation, graft the female donors cells in

a suceessful transplant will show very few circulating XY (if any) and a majority of XX in the male patient

an unsuccessful tranplant will show few XX in the male and many XY via FISH

Question 26

Genetics and Cancer summary

Answer 26

mutations may be inherited and/or acquired

somatic mutation is usually required for disease expression

disease is due to multistep process at somatic cell level

Question 27

inherited cancers summary

Answer 27

carrier parent has 50% chance of passing mutation

second mutation occurs at somatic level

risk is correlated to number and degree of affected relatives

inherited mutation -> increased RISK of acquiring disease, it is not guaranteed.

Question 28

Primary genetic causes of cancer can be linked to

many disease now have

new technologies are proving..

Answer 28

oncogenes/protooncogenes and tumor suppressor gene mutations

clinical testing available

new diagnostic methods and new treatments

Question 29

Which of the following is NOT a risk factor for cancer?

A. Trisomy 21

B. Smoking

C. Exposure to ultraviolet light

D. A constitutional translocation

E. All of the above ARE risk factors.

Answer 29

d.

A-C are definitely risk factors for cancer. A constitutional translocation is NOT. Constitutional translocations are inherited, usually as completely benign elements in a person’s chromosome complement. It may not be know the translocation even exists until it is detected as a result of a meiotic error. A translocation may arise de novo in a zygote, and again will be benign unless the breakpoints interrupt an important gene. The only type of translocation that was presented as a risk factor for cancer were acquired translocations that occurred in a clone of abnormal cells.

Question 30

Familial forms of cancer usually occur earlier in life because only a single mutation is required for disease expression. tf

Answer 30

false.

Familial cancers are usually due to mutations in tumor suppressor genes. Thus, this question is false for 2 reasons. First, TWO mutations in the specific tumor suppressor are required for disease expression. The statement says “ONLY a SINGLE mutation is required”, so that is completely wrong. Just because one mutation is inherited doesn’t mean that you discount it. It is one of the 2 mutations that are required for disease expression. Secondly, familial cancer requires mutations not only in the primary disease causing gene, but in several other genes as well (remember the cancer pathway from lecture). So, we are talking about 2 mutations in the primary tumor suppressor plus 2 mutations in 1-3 accessory tumor suppressors and single mutations in one or more proto-oncogenes. The point is that for cancer to occur, it is a complex process involving multiple genes and many mutations. To say that a single mutation is sufficient to cause any cancer is completely inaccurate. In familial cancer, one mutation is inherited but the second must occur at the somatic level. These cancers present relative early in life because the probability of the second mutation is high. If both mutations occur at the somatic level, the disease will occur later in life because it takes more time for both mutations to occur by chance.

Question 31

Hereditary non-polyposis colon cancer (HNPCC):

A. is the most common form of colon cancer.

B. is due to an inherited mutation of a tumor suppressor gene.

C. is correlated with the accumulation of random mutations throughout the genome.

D. is more likely to occur in women than in men.

E. results from errors in thymidine dimer excision.

Answer 31

C. is correlated with the accumulation of random mutations throughout the genome.

HNPCC is one of the rarest forms of colon cancer and is associated with mutations in genes that function in mismatch repair. These mutations result in a high level of random mutation throughout the genome. Significant accumulations of these mutations in colon tissue has been directly associated with the disease phenotype.

Question 32

The most common mechanism for altering a proto-oncogene to its oncogenic form is ___________________.

A. a deletion in the breakage cluster region (bcr).

B. the loss of one allele and duplication of the proto-oncogene.

C. a translocation between the proto-oncogene and one other gene.

D. a point mutation that results in the inactivation of one allele.

E. loss of heterozygosity of the proto-oncogene locus.

Answer 32

C. a translocation between the proto-oncogene and one other gene.

Transformation from proto-oncogene to “oncogene” is usually by amplification, translocation or point mutation. The activity/function of the proto-oncogene is changed (gain of function) and leads to tumorigenesis. B (loss and duplication), C (point mutation inactivating the gene), and E (loss of heterozygosity) are characteristic of tumor suppressors not proto-oncogenes.

Question 33

A hypothetical growth regulatory pathway is comprised of three proto-oncogenes and two tumor suppressor genes. What is the minimum number of mutations in this pathway that might lead to uncontrolled cell growth?

Answer 33

1. Numerous mutations in a combination of proto-oncogenes and tumor suppressor genes are generally required to cause a full-blown cancer with metastasis. However, a mutation in one allele of a proto-oncogene is sufficient to elevate its activity and cause uncontrolled cell GROWTH (proliferation). Therefore the answer is 1.

Question 34

Your patient, Rose, is 32 years old. Her father and sister were both diagnosed with retinoblastoma, and her father had to have one eye removed. Rose has never shown any signs of symptoms of the disease. She was recently married, and her husband, who has no family history of the disease, is concerned about the possibility of their children having retinoblastoma. What would you tell them about their risk for affected children? (retinoblastoma: 90% penetrance)

A. There is no risk that this couple would have an affected child.

B. The risk is equal to the population risk for sporadic disease.

C. The risk is equal to the population risk for a new mutation.

D. The risk is approximately 5% that Rose could pass the mutation on to a child.

E. There is a 10% chance of this couple having a child with retinoblastoma.

Answer 34

D. The risk is approximately 5% that Rose could pass the mutation on to a child.

Rose has two affected first degree relatives so the disease is inherited in this family. Her father is affected and has apparently transmitted the disease mutation to one daughter, so there is a 50% chance that he transmitted it to each of his children. Therefore, even though Rose did not manifest the disease, she has a 50% chance of being a carrier of the mutation. Since about 10% of individuals who inherit the mutation escape disease symptoms, the chance that Rose is a silent carrier is 5% so there is a risk that she could pass the mutation on to any of her children (answer D). If she is a carrier, she has a 50% chance of passing that mutation on to a child. The individual risk for a child to inherit the mutation is 2.5% (5% risk Rose is a carrier x 50% that she would pass the mutation on). Any child who inherits the mutation would have a 90% chance of expressing the disease, so the overall risk of this couple having an affected child is approximately 2.25% (5% that Rose is a carrier x 50% she would pass on a mutant allele x 90% that a child will express the disease.). If you want to more clearly establish these risks, you can do a Bayesian analysis which may change the numbers slightly.

Question 35

Carcinogenesis in a given individual is most commonly the result of inactivation of one of the many known tumor suppressors.

Answer 35

false. Carcinogenesis is also due to mutations of proto-oncogene. Furthermore, it is usually a multi-step process involving several genes.

Question 36

A proto-oncogene may be altered to its oncogenic form by

A. a deletion in the breakage cluster region (bcr).

B. the loss of one allele and duplication of the proto-oncogene.

C. a translocation between the proto-oncogene and one other gene.

D. a point mutation that results in the inactivation of one allele.

E. loss of heterozygosity of the proto-oncogene locus.

Answer 36

C. a translocation between the proto-oncogene and one other gene.

Transformation from proto-oncogene to “oncogene” is usually by amplification, translocation or point mutation. The activity/function of the proto-oncogene is changed and leads to tumorigenesis. B (loss and duplication), C (point mutation inactivating the gene), and E (loss of heterozygosity) are characteristic of tumor suppressors not proto-oncogenes.

Question 37

Which of the following is NOT a risk factor for cancer?

A. Trisomy 21

B. Smoking

C. Exposure to ultraviolet light

D. A constitutional translocation

E. All of the above ARE risk factors.

Answer 37

A-C are definitely risk factors for cancer. A constitutional translocation is NOT. Constitutional translocations are inherited, usually as completely benign elements in a person’s chromosome complement. It may not be know the translocation even exists until it is detected as a result of a meiotic error. A translocation may arise de novo in a zygote, and again will be benign unless the breakpoints interrupt an important gene. The only type of translocation that was presented as a risk factor for cancer were acquired translocations that occurred in a clone of abnormal cells

Question 38

Familial forms of cancer usually occur earlier in life because only a single mutation is required for disease expression. T.F

Answer 38

false, just purposely poorly worded

Familial cancers are usually due to mutations in tumor suppressor genes. Thus, this question is false for 2 reasons. First, TWO mutations in the specific tumor suppressor are required for disease expression. The statement says “ONLY a SINGLE mutation is required”, so that is completely wrong. Just because one mutation is inherited doesn’t mean that you discount it. It is one of the 2 mutations that are required for disease expression. Secondly, familial cancer requires mutations not only in the primary disease causing gene, but in several other genes as well (remember the cancer pathway from lecture). So, we are talking about 2 mutations in the primary tumor suppressor plus 2 mutations in 1-3 accessory tumor suppressors and single mutations in one or more proto-oncogenes. The point is that for cancer to occur, it is a complex process involving multiple genes and many mutations. To say that a single mutation is sufficient to cause any cancer is completely inaccurate. In familial cancer, one mutation is inherited but the second must occur at the somatic level. These cancers present relative early in life because the probability of the second mutation is high. If both mutations occur at the somatic level, the disease will occur later in life because it takes more time for both mutations to occur by chance.