CANCER GENETICS

Question 1

Define cancer.

Answer 1

Group of cells that display uncontrolled growth, invasion that intrudes or destroys adjacent tissue and often spreads to other tissues via the lymphatic system or blood stream.

Question 2

Describe cancer as a genetic disease.

Answer 2

All cancers involve DNA mutations. Cancer is a complex, multifactorial gene disorder involving many kinds of mutations and environmental factors.

Question 3

What are the two broad classes of mutations that need to be considered in cancer genetics?

Answer 3

Germline mutations and somatic mutations.

Question 4

What are germ line mutations?

Answer 4

Mutation in egg or sperm. All cells descended from the mutant gamete carry the mutation, which can be passed to subsequent offspring resulting in cancer family syndromes.

Question 5

What are somatic mutations?

Answer 5

Occur in non-germline tissue and are non-heritable. Also referred to as sporadic mutations.

Question 6

describe de novo mutations.

Answer 6

New mutation occurring in a germ cell and passed on to offspring. The mutation phenotype is only present in the offspring, and does not affect individual in whom the mutation occurred.
ALL germline mutations initially originate as de novo mutations.

Question 7

What are 2 mechanisms that increase the likelihood of a cell acquiring 6 or 7 independent mutations?

Answer 7

1. mutations that increase cell numbers: usually involve genes that regulate cell cycle and proliferation, or genes involved in cell death.
2. Mutations that affect the entire genome: mutations in enzymes such as DNA repair enzymes.

Question 8

What are the 2 broad gene classes involved in controlling genome integrity?

Answer 8

GATEKEEPERS: oncogenes and some tumour suppressor genes. cells with mutations in these genes increase in numbers more than other cells, procifing additional targets for further mutation.
CARETAKERS: DNA dame response genes. If these genes fail, gatekeeper mutations or any other mutations cannot be repaired.

Question 9

Describe the founder effect.

Answer 9

Occurs when a relatively small population is isolated from the rest of the population and an individual (founder) in the isolated population carries or develops a germ line mutation that is rare in the general population.
Later generations of the isolated population will have a higher frequency of the mutation because of reproductive isolation.
Migration or isolation (marked population decrease) causes a genetic bottleneck, leading to the founder effect.

Question 10

What is a pro to-oncogene?

Answer 10

Encode proteins that regulate cell growth.

Question 11

What is an oncogene?

Answer 11

A mutated or over-expressed proto-oncogene causing unregulated cell growth or transformation.
Expression is usually dominant, and they are involved in sporadic cancers.
A few oncogenes can predispose to hereditary cancer syndromes.

Question 12

Give an example of a proto-oncogene, and describe the results of mutation.

Answer 12

RET is a proto-oncogene. Loss-of-function mutations lead to Hirschsprung’s disease, and gain of function mutations may cause medullary thyroid carcinoma, and multiple endocrine neoplasia (hereditary cancer syndrome).

Question 13

Describe tumor suppressor genes.

Answer 13

Act as “brakes” against excessive growth.
Repress genes that continue the cell cycle, initiate apoptosis if DNA damage cannot be repaired, cause cell adhesion to prevent metastasis.

Question 14

Describe the genetic aspect of tumour suppressor genes and their mutations.

Answer 14

Tumour supressor gene mutations are generally recessive at the cell level.
1st mutation: affects one allele and predisposes an individual to cancer (results in susceptible carriers).

2nd mutation: affects the other allele and causes cancer.

Question 15

Give an example of a tumour suppressor gene and describe it.

Answer 15

P53.
More than 50% of human tumours contain mutations in P53. germ line mutation may cause Li-Fraumeni syndrome and an increased susceptibility to cancer. Several type of cancer are involved, often appears at young ages and occurs multiple times throughout life.

Question 16

Describe the two-hit hypothesis.

Answer 16

genes where both copies need to be abnormal in order for an effect to be observed in the phenotype, thus “two hits”. The chances of this are very small.
However, if one copy is already abnormal for any reason, only one more “hit” will be required to affect the phenotype. This is much more common.

Question 17

Describe the genetic aspects of tumour suppressors and cancer.

Answer 17

Defects in tumour suppressor genes are typically recessive, however cancer susceptibility is considered to be autosomal dominant (because “first hit” is inherited in an autosomal dominant fashion).

Question 18

Describe the loss of heterozygocity.

Answer 18

Any genetic mechanism that leaves a cell with only one functional allele at a locus, allowing previously recessive phenotypes to appear. This can lead to cancer id the affected region contains a tumour suppressor gene.
Common occurrence in cancer.

Question 19

What are some mechanisms of loss of heterozygocity?

Answer 19

chromosome loss
deletion
unbalanced translocation
loss and reduplication
mitotic recombination
point mutation inactivating 2nd allele.

Question 20

How does LOH result in cancer?

Answer 20

After an inactivation mutation in an allele of a tumour suppressor gene in the parents germ cell, it is passed on to the offspring (heterozygous). Many people remain healthy with such a loss, because there is still one functional gene left on the other chromosome.
In oncology, LOH occurs when the remaining functional allele in a somatic cell of the offspring becomes inactivated. This could cause a normal tumour suppressor to no longer be produces, which could result in the development of cancer.

Question 21

Describe Familial Adenomatous Polyposis (FAP).

Answer 21

Type of colorectal cancer caused by mutations in APC gene. Autosomal dominant inheritance.
Mutation results in hundreds to thousands of clonal expansions in the form of benign polyps by the time the person is in their 20’2-30s. Spome polyps progress to cancer if additional mutations occur.

Question 22

Describe DNA Mismatch Repair (MMR) genes.

Answer 22

eliminate base-base mismatches and insertion-deletion loops which arise as a result of DNA polymerase slippage.
correct DNA biosynthesis errors, ensure fidelity of genetic recombination and participate in checkpoint and apoptotic responses.
Inactivation of these genes speeds the accumulation of mutations in other critical genes, and greatly increases the risk of developing cancer.

Question 23

Describe incomplete penetrance and age-specific penetrance.

Answer 23

Some carriers of a dominant allele may not express the trait. Penetrance is often age-related.

Question 24

What are the 2 key factors affecting penetrance of cancer susceptibility alleles?

Answer 24

1. genetic factors: other genes can affect penetrance of germ line mutation.
2. Environmental factors: carcinogens, viruses, lifestyle, hormones. Genetic environmental factors may increase penetrance (risk factors) or decrease penetrance (protective factors)

Question 25

What are the implications of incomplete penetrance on genetic testing?

Answer 25

Mutations with incomplete penetrance will increase disease risk, but will not necessarily lead to cancer. this complicates decisions relating to genetic testing.
Detection of a mutation may create unnecessary anxiety in people who may not develop disease, and decrease the cost effectiveness of screening programs.
However, knowing you carry a mutation may allow disease risk to be reduced by modifying other factors that affect risk.

Question 26

What are the benefits of testing for DNA repair gene mutations?

Answer 26

allow identification of mutation carriers.
Identify non-carriers in affected families.
For some cancers, surveillance of at-risk people lowers mortality
Allows carriers to make informed decisions about surgery or other treatments.

Question 27

What are the limitations of testing for DNA repair gene mutations

Answer 27

limited immediate advantage to people with cancer
limited sensitivity due to genetic heterogeneity
limited sensitivity for technical reasons
non-carriers still at risk of getting sporadic cancer
surveillance may not always reduce mortality.