Cancer

Learning Objectives

By the end of this class you should understand:

The steps required for a cell to become cancerous

The link between genes, mutation and cancer

The models of retinoblastoma, breast cancer, and colon cancer

Translocation events that create a risk for cancer

Treatments for cancer including new ones currently under study

What is Cancer?

Cancer is the result of a single cell that is undesirably and constantly reproducing

Any cell in the body can become cancerous But some are more

likely candidates than others!

Cell Replication

There are molecular mechanisms (checkpoints) that prevent a cell from constantly undergoing mitosis Occur at G1/S and G2/M Cells also cannot

replicate without an external signal

Cancer Checklist

To become cancerous, a cell must: Have its control genes fail

via mutation (fresh or inherited)

Have its go-ahead signal stuck in the “on” position

Develop expression of telomerase if it was not already a stem cell

This is a long list!

Typically, to facilitate the checklist being met, cancer cells also have a failure of mutation repair This begins to

prompt many, many mutations

Types of Cancer

A cell that has begun to undergo mitosis until it has exhausted all its blood supply forms a tumor A lump, sometimes hard,

sometimes just an outgrowth of flesh

If no further mutation takes place, it is typically benign (not harmful)

Dangerous Cancer

For cancer to become malignant, two additional steps must be met: Angiogenesis

(ability to create new blood vessels to feed the tumor)

Metastasis (ability to spread through tissues and blood)

Cancer Genes

Cancer genes fall into two major categories: Tumor-suppressor

genes normally block mitosis and must be knocked out for cancer to occur

Proto-oncogenes normally pass on signals to grow, and must be stuck in the “on” mode

Tumor-Suppressor Genes p53 is the classic tumor-

suppressor gene Produces a protein that

blocks mitosis when DNA is damaged

Protein also induces apoptosis (cell suicide) if genome is irretrievable

p53 knockouts are nearly universal in cancer

Tumor-Suppressor Gene

RB1 is another tumor-suppressor gene found in many cells

Produces a protein called pRB that blocks cell cycle

RB1 failure is linked to retinoblastoma and other cancers

Proto-Oncogenes

ras is the classic proto-oncogene

Codes for a protein that passes a growth factor signal to the nucleus

If mutates in amino acid 12 or 61, fails to switch off and cell is permanently stimulated

ras Mutations

Cancer Categories There are hundreds of kinds of cancer, but

some are clearly more common than others Epithelial cancers are most common for two

reasons:

– Epithelial tissue is exposed to the outside more

– Epithelial stem cells are very common (e.g. skin)

Model Cancers

Model cancers are especially well-studied for their genetics

– Often studied due to being relatively common

Models discussed here:

– Retinoblastoma

– Breast Cancer

– Colon Cancer

– Leukemia (CML)

Retinoblastoma

Familial retinoblastoma is caused by having a bad RB1 gene

– Typically individuals are heterozygous

– If the “good” allele is deactivated by any mutation, this loss of heterozygosity results in cancer in affected organ

Breast Cancer

Breast cancer is very common, so a major study searched for commonly mutated genes in all breast cancer cells

– BReast CAncer genes BRCA1 and BRCA2 were isolated

– These were patended by Myriad, patent recently overturned

BRCA1 and BRCA2

The BRCA genes are for DNA repair BRCA1 activates when a break in DNA is

discovered

– Inactivated BRCA1 protein cannot bind to Rap80 and fix the DNA

Loss of heterozygosity occurs in up to 85% of women with one mutant allele, resulting in most of the heritable breast cancer cases

– Still only about 20% of all breast cancer cases

Colon Cancer

Two major pathways for colon cancer:

– Familial adenomatous polyposis (chromosomal instability) or FAP

– Hereditary nonpolyposis colon cancer (failure to repair DNA) or HNPCC

FAP Colon Cancer

In FAP, polyps forms much more than usual, increasing mitosis and risk of cancer

Identifying FAP genes helped overall understanding of cancer

Sequential Gene Failure

HNP Colon Cancer HNPCC is caused by

failed DNA repair enzymes that work during mitosis

Even without polyps, mutation rate in colon is increased and cancer risk increases

Leukemia

Chronic Myelogenous Leukemia is often caused by a particular translocation

– Chromosomes 9q and 22q

– The “Philadelphia Chromosome”

The exact point of translocation creates a hybrid gene

– Combination of C-ABL and BCR genes

Philadelphia Chromosome

Hybrid Gene The C-ABL gene and the

BCR gene produce a single protein that contains properties of both

– C-ABL is for signal transduction

– BCR activates and deactivates proteins

The hybrid protein signals white blood cells to constantly multiply

Cancer Treatments

Two standard treatments today are radiation therapy and chemotherapy

Both work by poisoning cells during mitosis

– Since cancer cells are constantly undergoing mitosis they are affected the most

– This is why you also lose your hair

Targeted Therapy

A new model of cancer treatment is to determine what protein in the cancer is constantly signaling mitosis and block it

The C-ABL/BCR hybrid can be deactivated by a special messenger molecule

Targeted Therapy

Works better in earlier stages

– Many late-stage cancer cells have so many mutations they will not respond to targeted therapy

Provides promising less-destructive ways to cure cancer in the future

Have a good weekend!

Have you picked your genetic disorder yet?