Basic Principles of Cancer Genetics

Question 1

What are the objectives of cancer genetics?

Answer 1

1. Identifying individuals at increased risk for cancer (due to an inherited predisposition to cancer) - before it develops.
2. Offering the appropriate screening, which allows for early diagnosis and treatment of cancer.
3. Offering genetic testing and counseling to relatives at risk .

Question 2

Define - neoplasia.

Answer 2

An abnormal growth produced by an imbalance between normal cellular proliferation and normal cellular attrition. A neoplasm may be benign or malignant (cancer).

Question 3

What is cellular proliferation?

Answer 3

When cells undergo mitosis as a part of the cell cycle.

Question 4

What is cellular attrition?

Answer 4

When cells undergo apoptosis (i.e. programmed cell death).

Question 5

What are the characteristics of a benign tumor (non-cancerous neoplasm)?

Answer 5

• No local invasion.

- Does not metastasize.

Question 6

What are the characteristics of a malignant tumor (cancerous neoplasm)?

Answer 6

• Local invasion of the neighboring tissues that surround the primary/original site.
• Can metastasize (spread to distant sites).

Question 7

What are the 3 classes of cancer?

Answer 7

1. Sarcomas: malignant neoplasms which originate in mesenchymal tissue, such as bone, muscle, connective tissue, or nervous system.
2. Carcinomas: malignant neoplasms which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts.
3. Hematopoietic and lymphoid: malignant neoplasms, such as leukemia and lymphoma which spread throughout the bone marrow, lymphatic system, and peripheral blood.

Question 8

How are tumors classified within each of the major groups?

Answer 8

By:

1. Site
2. Tissue type
3. Histological appearance
4. Degree of malignancy
5. Chromosomal aneuploidy
6. Genetic mutation
7. Abnormalities in gene expression

Question 9

Cancer is fundamentally a genetic disease - true or false?

Answer 9

True.

Question 10

Define - passenger gene mutation.

Answer 10

• Accounts for the vast majority of somatic mutations in cancers.
• They appear to have occurred at random as the cancer developed and are not recurrent in particular types of cancer.
• These mutations do not directly cause the cancer to develop or progress.

Question 11

Define - driver gene.

Answer 11

• These are genes that are presumed to be involved in the development or progression of the cancer itself.
• This is based on the fact that somatic mutations in this gene, have repeatedly been found in many samples of the same type of cancer or multiple different types of cancer.
• The mutations are too frequent to be random events.

Question 12

What is the NATURE and FREQUENCY of replication errors?

Answer 12

Replication errors result in thousands of new single nucleotide or small insertion/deletion mutations in the DNA of every cell of the organism.

Question 13

What can increase the rate of replication errors / mutations?

Answer 13

Carcinogens such as cigarette smoke, ultraviolet radiation, and X-ray irradiation.

Question 14

What initiates the oncogenic process?

Answer 14

A causative mutation in a critical driver gene.

Question 15

Give an example of a chromosomal driver mutation.

Answer 15

BCR - ABL translocation in chronic myelogenous leukemia (CML).

Question 16

Define - chromosome shattering.

Answer 16

Phenomenon seen in some cancer cells in which the chromosomeS break into numerous pieces and rejoin forming novel and complex chromosome rearrangements. The mechanism is unknown.

Question 17

Define - gene amplification.

Answer 17

Many copies of the same gene as a result of multiplication of a chromosome segment.

Question 18

List the spectrum of driver gene mutations, in general.

Answer 18

1. Single nucleotide change.
2. Small insertion/deletion.
3. Chromosomal abnormalities:
   - Translocations
   - Chromosome shattering
   - Deletions and duplications resulting in loss of function or gain of function of one or more driver gene.

Question 19

Table 15 - 1 on page 311 of Thompson and Thompson

Answer 19

Review

Question 20

Define - oncomirs.

Answer 20

MicroRNAs (miRNAs) - derived from noncoding RNAs - which contribute to oncogenesis by impacting gene expression.

Question 21

What is the SWI/SNF complex?

Answer 21

SWI/SNF (SWItch/Sucrose Non-Fermentable) is a sub-familiy of ATP-dependent chromatin remodeling complexes.

Question 22

What are the two “functional” categories of both classes of driver genes?

Answer 22

1. Activated oncogenes

2. Tumor suppressor genes

Question 23

Define - proto-oncogene.

Answer 23

A normal gene involved in cell division or proliferation that may become activated by a mutation or other mechanism such as overexpression or amplification - to become an oncogene.

Question 24

Define - oncogene.

Answer 24

A DOMINANTLY acting gene RESPONSIBLE for tumor development, which resulted from activation of a proto-oncogene by a mutation (or other mechanism such as overexpression or amplification) of a SINGLE allele.

Question 25

What is the pathogenic mechanism of an activated oncogene?

Answer 25

• Excessive level of activity.

- Stimulating cellular proliferation or inhibiting apoptosis.

Question 26

Define - tumor suppressor gene (TSG).

Answer 26

A normal gene involved in the REGULATION of cellular proliferation. Loss of function mutations in BOTH alleles can lead to tumor development.

Question 27

What is the pathogenic mechanism of a mutated tumor suppressor gene?

Answer 27

Loss of expression.

Question 28

Of the two “functional” categories of both classes of driver genes, which is more common?

Answer 28

Tumor suppressor gene.

Question 29

List the possible mutations that lead to activation of a proto-oncogene and “tumor initiation”.

Answer 29

1. Point mutations which cause dysregulation or hyperactivity of a protein:
   - If occurring in a coding region, an abnormal protein is produced;
   - If occurring in a regulatory region, excessive amount of protein is produced.
2. Chromosome translocations that:
   - Drive overexpression of a gene, or
   - Produce a novel protein product with oncogenic properties.
3. Gene amplification events that create an abundance of the encoded mRNA and excessive amount of protein product.

Question 30

List the possible mutations that lead to loss of function of a tumor suppressor gene and “tumor initiation”.

Answer 30

1. Missense mutations.
2. Nonsense mutations.
3. Frameshift mutations.
4. Dominant negative mutation of one allele.
5. Gene deletions (due to loss of part of a chromosome or its entirety).
6. Epigenomic transcriptional silencing by:
   - Promoter methylation, or
   - Altered chromatin conformation
7. Translational silencing by:
   - miRNAs, or
   - Disturbances in other components of the translational machinery

Question 31

Individual tumors show cellular heterogeneity - true or false?

Answer 31

True.

Question 32

The profile of mutations and epigenomic changes can differ between the primary and its metastases, between different metastases, and even between the cells of the original tumor or within a single metastasis.

Tumor progression occurs as a result of accumulating additional genetic damage, through mutations or epigenetic silencing, of driver genes that encode the machinery that repairs damaged DNA and maintains cytogenetic normality.

True or false?

Answer 32

True.

Question 33

Define - somatic mutation.

Answer 33

A mutation occurring in a somatic cell rather than in the germline.