1. Genetics Of Cancer

2. The Big Picture
A few cells probably escape the controls of the cell cycle in each of us, but are usually silenced by the immune system.
In one in three of us, though, such errant cells continue to divide and invade healthy tissue, causing cancer.
The many forms of cancer reflect mutations in particular cell types

3. History of Cancer
Egyptian mummies from 3000 B.C. show signs of cancerous tumors
By 1600 B.C. Egyptians were attempting to treat cancer by cutting or burning off the growths
By 300 B.C. Hippocrates had described several types of tumors and coined the term “cancer” to describe the crab-like shape of a tumor cell.

4. What is cancer? Overview
Collection of diseases that reflect malfunction of the cell cycle that can be set in motion by environmental factors
Sequences of mutations in somatic cells and gene expression changes underlie the progression of cancer as it spreads
Diagnosis and treatment is becoming more individualized due to genetic and genomic approaches
Only about 10% of cases are inherited as single gene disorders where faulty instructions are found in every cell.
Cancer is usually a genetic disease at the cellular level, but not the whole body level-as mutations in cancer causing genes generally affect a few somatic cells over a lifetime

5. The complications of being Specialized
Cancers are a complication of our being both multicelluar and specialized…
Cells must follow a schedule of mitosis-the cell cycle so that organs and other body parts either:
grow appropriately during childhood,
Stay a particular size and shape
Repair damage by replacing tissue
Cell that escapes the normal controls on its division
Forms a tumor in solid tissues
Divides more frequently and takes over normal cells in non-solid tissues like blood
Tumors are
Benign if it grows in place but does not spread into or ‘invade’ surrounding tissues
Malignant, or cancerous, if it infiltrates surrounding tissue
Metastatic if they send parts of them selves into the bloodstream or lymph and are transported as ‘seeds’ to other tissues

6. Oncogenes and tumor suppressor genes
A gene that causes cancer when appropriately activated
More than 100 have been discovered by focusing on genes in chromosome regions whose protein products could affect cell cycle control
Tumor Suppressor Genes
Cause cancer when they are deleted or inactivated
More that 30 have been identified
Normally function to keep cell cycle running at appropriate rate for a particular cell type under particular conditions

7. Loss of Cell Cycle Control
Timing, rate and number of mitoses a cell undergoes depend on protein growth factors and signaling molecules outside the cell and on transcription factors within
These biochemicals are under genetic controls, so is the cell cycle
The discovery of the checkpoints reveal how cancer can begin
A mutation in a gene that normally halts or slows the cycle can lift the constraint leading to inappropriate mitosis
Failure to pause long enough to repair DNA can allow a mutation in an oncogene or tumor suppressor gene to persist

8. Cancer and Telomere Length
Loss of control of telemere
length may also contribute to
cancer
Normally, telemere repeats are lost as the cell matures from nucleotides per cell division. The more specialized the cell, the shorter its telemeres; like nerve and muscle. Sperm and oocyte are very long
The enzyme telemerase keeps telemers long by adding 6-base repeats(TTAGGG)…in specialized cells enzyme is turned off, signaling a halt to cell division when they reach a certain size
In cancer cells, the enzyme is turned back on and releases the normal brake on rapid cell division
The longer the telemeres in cancer cells the more advanced the disease

9. Inherited versus Sporadic Cancer
SPORATIC
INHERITED
Most cancers
Found only in cells of affected tissues
Somatic mutations
May result from single dominant mutation or 2 recessive mutations in the same gene causing loss of cell cycle control
Susceptibility is not directly passed to offspring
Rare, but, high penetrance, occur earlier in life
Cancer susceptibility is directly passed to offspring
Germline mutations are in every cell, including gametes
Cancer develops when second mutation occurs in the other allele in a somatic cell in the affected body part

10. Lung Cancer: from both perspectives
Germline mutations may explain why some heavy smokers develop lung cancer while others do not; unlucky ones have may have inherited a susceptibility allele in every cell
Years of exposure to carcinogens eventually cause a mutation in a tumor suppressor gene or oncogene of a lung cell
Without the susceptibility gene, two such somatic mutations are necessary to trigger the cancer
This too can be the result of exposure to carcinogens, but, it takes longer for the two events to occur than one

11. Characteristics of cancer cells

13. Cancer Cells…
Grow alarmingly fast: by time tumor is the size of a pea= billions of cells are actively dividing, eventually grows faster than surrounding tissue because greater proportion if cells are dividing
Look different than a normal cell: rounder because membrane is more fluid, contain different antigens on surface
Are heritable: when cancer cell divides all daughter cells are cancerous
Is transplantable: if injected into healthy tissue of same species it will proliferate
Are differentiated: less specialized than normal cells near it, cancer cells pile up and crowd other cells
Are invasive: have surface structures that enable them to squeeze into any space, grow irregularly as they invade tissue spaces
Metastasize: eventually reach the bloodstream or lymph and are carried to other parts of the body
Stimulates angiogenesis the tumor causes nearby capillaries to sprout new branches to provide the tumor with oxygen and nutrients

15. Breast Cancer: BRCA1 and BRCA2
Inheritance of germline mutation and then having a somatic mutation occur in a breast cell
Only 5% of all breast cancers are familial, caused by mutations in any of more than a dozen different genes
Mutations in DNA repair genes cause this type of cancer
BRCA(breast cancer predisposition gene)1 and 2 are major susceptibility genes; account for 15-20% of familial cases
Deletion-frame shift mutations result in shortened proteins, that form a complex that breaks both strands of DNA at same site, cutting chromosome making translocations and deletions possible
Inheritance is autosomal dominant with incomplete penetrance

16. Cancer cells that look alike may be genetically distinct…take leukemia cells

17. Personalization of cancer Diagnosis and treatment
Oldest treatment is surgery to remove the tumor
Radiation and chemotherapy which kill all cells that divide rapidly, however, also affect healthy cells: digestive tract, hair follicles, bone marrow
Newer treatments target receptors on cancer cells, block telomerase, stimulate differentiation; or attack a tumor’s blood supply

18. Examples of cancer
Genetic vs environmental