Biology 205 Genes and Cancer.

I. Cancer.

A. Distinction between Tumor and Cancer

1. Transformation - Process by which cell growth/development becomes unconstrained

2. Cancer - resulting cells spread to other tissues - metastasis

3. Benign (no metastasis) usually not life threatening

4. Oncogenesis- (onkos = "mass")

B. Factors in cancer

1. Single gene mutations

2. Chromosomal changes

3. Environmental Carcinogens

4. Abnormal hormonal levels

5. Viruses

C. Sporadic vs familial cancers...only 1% of cancer cases clearly familial

II. Characteristics of cancer cells

A. Loss of contact inhibition

B. Failure to undergo apoptosis

C. High levels of telomerase

D. Clonal - result from a single cell.

1. Evidenced by expression of only one X chromosome in the cells in a cancer

2. But population of cells becomes genetically heterogeneous due to genetic instability

a. mutations, gene amplification aneuploidy

b. selection for cells capable of high proliferation and metastasis

D. Most cancers relate to mutations involving control of cell cycle.

E. Viewed today as resulting from accumulated mutations...see figure 14.1

III Types of genes involved in cancer

A. Oncogenes- gain in function genes.

1. Result from mutations that cause over expression of a product involved in regulating the cell cycle.

2. Normal forms of these genes are called proto-oncogenes

3. Example:Cyclin D/ Cdk4. Excessive production leads to early entry into S phase.

a. found in 35% of esophageal cancers

b. Amplification of cyclin D gene in 15% of breast cancer but over- expression in 50% of breast cancers!

5. Growth factor receptor gene amplification

6. Ras: a small signaling protein.

B. Tumor suppressor genes

1. Normally inhibit cell division

2. When inactivated, cell division become uncontrolled.

3. Example: Retinoblastoma (p 345-346) note Hereditary Vs Sporadic forms.

4. RB gene on chromosome 13 codes for pRB protein.

IV. Genetics of colon cancer

A. Development of cancer multi-step process

B. Features of genetics

1. requires 5 - 7 mutations in a single cell or cell line

2. Both the order and number of mutations in different genes important

V. Genomic changes and cancer

A. Hereditary non-polyp colon cancer caused by mutation in gene related to DNA repair

1. In turn mutations arise in proto-oncogenes and tumor suppresser genes

2. Suggests gate-keeper Vs caretaker gene concept

B. Chromosomal changes and cancer

1. Extra copies of chromosome 21 in Down's lead to increased Leukemia

2. Translocation between chromosome 9 and 22 leads to Philadelphia Syndrome. See table 14.10 for other examples

3. Appears to involve so called hybrid genes at translocation break points

V. Cancer and environment Epidemiology

A. Asbestos case study

B. 50% of al cancers related to environmental factors

C. Also may be synergistic interactions

D. Environmental causes

1. Radiation ionizing Vs non ionizing

2. Mutagens often carcinogens...Ames test. See page 360 Guest essay

3. Diet and behavioral choices:

a. Risk of colon cancer related to intake of animal fat

b. Smoking

4. Correlation is not causation...but don't ignore correlation!

VI. Retroviruses and cancer

A. Retrovirus multiplication cycle.

B. Mechanisms of viral cancer causes

1. transducing viruses carry oncogenes example Rous sacoma viruses in chickens

2. integration of proviral DNA near proto-oncogene - expression now conrolled by viral promoter regions(rare)

3. suppresion of immune system(HIV)

4. DNA virus do not carry oncogenes

a. viral DNA sometimes gets integrted into host genome

b. expression of viral gene activating DNA synthesis causes host cell to go into S phase.

3. Papilloma viruses (HPV-16, 18) cause cervical cancer

11/12/02 pgd

revised 04/17/03