Genes and CancerChapter 12

Cancer Is a Genetic Disorder of Somatic Cells

Somatic cells – any cell of the body except sperm and egg

Cancer is a complex disease characterized by two main properties:

Uncontrolled cell division The ability of these cells to spread to other sites in

the body (metastasis) Each year, more than one million new cancer

cases are diagnosed and approximately 500,000 people will die from the disease

Estimated Cases of Cancer in the US, 2015

Age is a Leading Risk Factor for Cancer10,000

1,000

100

KEY10

Can

cer d

eath

s (p

er 1

00,0

00)

FemaleMale

1

<1 1– 5–9

10 15–1

920 25

–34

35– 45–5

455

– 75–8

4

–24

65–7

4

85+4

–14 44 64

Age groups in years

Cancer and Genetics

A predisposition to more than 50 forms of cancer are inherited to one degree or another

Most chemicals that cause cancer are also mutagens

Some viruses carry genes that promote cancer Gardasil is effective against HPV types 16 and

18 which cause approximately 70% of cervical cancers, and against HPV types 6 and 11 which cause approximately 90% of genital warts.

Specific chromosomal changes are found in certain cancers

Mutations are the ultimate cause of cancer

Cancer Begins in a Single Cell

Cancer cells are clonal descendants from one mutant cell The cell accumulates specific mutations over a

long period of time Cancer cells that escape control of the cell cycle

divide continually Mutations continue to accumulate

Cancer cell scan can be either: Non-invasive (benign) or Invasive and spread to other sites (metastatic)

ANIMATION: Cancer and metastasis

To play movie you must be in Slide Show ModePC Users: Please wait for content to load, then click to play

Mac Users: CLICK HERE

Metastasis

Cancer cells break away from their original tissue.

The metastasizing cells become attached to the wall of a blood vessel or lymph vessel. They secrete digestive enzymes to create an opening. Then they cross the wall at the breach.

Cancer cells creep or tumble along inside blood vessels, then leave the bloodstream the same way they got in. They start new tumors in new tissues.

2

1

3

Cancers: Sporadic and Inherited

Sporadic cancer - Cancer caused by accumulation of a number of mutations in somatic cells Mutation occurs in a single somatic cell Additional mutations accumulate

Inherited cancer syndromes - Inherited mutant genes cause a predisposition to cancer Mutations are carried in all cells in a heterozygous

state The normal allele is lost in the cancer cell (loss of

heterozygosity)

3D ANIMATION: Cancer

ANIMATION: The cell cycle and cancer—Phases

To play movie you must be in Slide Show ModePC Users: Please wait for content to load, then click to play

Mac Users: CLICK HERE

file:///D:/Media/PowerPoint_Lectures/chapter12/videos_animations/4_2_1.html

ANIMATION: The cell cycle and cancer—Growth factor control

To play movie you must be in Slide Show ModePC Users: Please wait for content to load, then click to play

Mac Users: CLICK HERE

file:///D:/Media/PowerPoint_Lectures/chapter12/videos_animations/4_2_2.html

The Eukaryotic Cell Cycle

G1/S Checkpoint Cell proceeds to S phase or enters inactive G0 state

G1 Interval of cell growth before DNA replication (chromosomes unduplicated)

S Interval of cell growth when DNA replication is completed (chromosomes duplicated)

Each daughter cell starts interphase

CYTOKINESIS

Telophase

M Checkpoint Cell monitors attachment of spindle fibers to chromosomes

Proph

ase G2

Interval following DNA replication; cell prepares to divideIn

terp

hase

end

s fo

r par

ent c

ell

G2/M Checkpoint Cell monitors completion of DNA synthesis and DNA damage

MetaphaseAnaphase

Tumor Suppressor Genes

Tumor suppressor genes decrease cell division Encode proteins that

suppress cell division and regulate the cell cycle

These gene products act at control points in the cell cycle, at G1/S or G2/M

Deletion or inactivation of these products cause cells to divide continuously

Oncogenes

Oncogenes increase cell division Proto-oncogenes - Genes that initiate or

maintain cell division May become cancer genes (oncogenes) by

mutation Oncogenes - Genes that induce or continue

uncontrolled cell proliferation

Proto-Oncogenes To Oncogenes

Oncogenes are permanently switched on proto-oncogenes that cause uncontrolled cell division A single base change can produce an altered

gene product (A,T,C,G) Mutations can increase the number of copies of a

normal gene

Retinoblastoma

A malignant tumor of the eye arising in retinoblasts (embryonic retinal cells that disappear at about 2 years of age)

Usually occurs only in children Mature retinal cells do not

transform into tumors Associated with a deletion in the

long arm of chromosome 13 The responsible gene, Rb, is

located on chromosome 13

Two Types of Retinoblastoma

Familial retinoblastoma Individuals inherit one mutant copy of RB1 gene 85% to 95% chance of developing the disease

Sporadic retinoblastoma Mutations of both copies of RB1 gene occur in a

single cell Occurs with a frequency of approximately 1 in

15,000

The RB1 Gene The tumor-suppressing protein

pRB (retinoblastoma protein) controls the G1/S transition in the cell cycle G1/S Transition – cell either

enters the next phase of the cycle or enters a nondividing state called G-0.

Without pRB, cell division is uncontrolled

Mutant Cancer Genes

Many basic properties of cancer result from the inability of cancer cells to repair damage to DNA High rates of mutation, chromosomal

abnormalities, and genomic instability DNA repair genes are now recognized as a

class of cancer-related genes (along with tumor suppressor genes and proto-oncogenes)

Mutations in BRCA1 and BRCA2 genes can predispose women to breast and ovarian cancer

Genetic Predisposition to Cancer

BRCA2

BRCA1

13 17

BRCA1 and BRCA2 are DNA Repair Genes

BRCA1 protein, found only in the nucleus, is activated when DNA is damaged Stops DNA replication Binds to Rap80 protein to identify DNA damage

and initiate repair Mutant forms are unable to repair DNA Mutations accumulate; cell become cancerous

Male Breast Cancer Very rare Approximately 2,000 cases per year Men who inherit mutant BRCA1 or BRCA2 have

an 80-fold elevated risk

Colon Cancer: a Genetic Model for Cancer Cancer is a multistep process that requires a number of

specific mutations Study of colon cancer provides insight into the number

and order of steps involved in transforming normal cells into cancer cells

Starts as a benign tumor that later becomes malignant Six or more mutations required to initiate cancer

There are two pathways to colon cancer related to genetic predispositions1. Familial adenomatous polyposis (FAP)2. Hereditary nonpolyposis colon cancer (HNPCC)

A Multi-step Model For Colon Cancer

Chromosome 5q 12p 18q 17p OtherAlteration Mutation Deletion Deletion Mutations

Gene APC K-RAS DCC p53

Normal colon

epithelium

Polyp Intermediate adenoma

Late adenoma with villi

Colon cancer

Metastatic cancer

Mutation

Colon and Rectal Cancer in the US

1. Familial adenomatous polyposis (FAP)

An autosomal dominant trait resulting in the development of polyps and benign growths in the colon

Polyps often develop into malignant growths and cause cancer of the colon and/or rectum Small clusters of dividing cells on the lining of

colon

2. Hereditary Nonpolyposis Colon Cancer (HNPCC)

An autosomal dominant trait associated with genomic instability of microsatellite DNA sequences and a form of colon cancer Is caused by DNA repair defects Microsatellites: DNA sequences, 2 to 9

nucleotides long, that are repeated thousands of times and located on many chromosomes

Clusters are called simple sequence repeats (SSRs) or short tandem repeats (STRs)

Mutations in MSH2 or MLH1 genes destabilize the genome, generating a cascade of mutations in DNA microsatellites

HNPCC is due to DNA Repair Defect

Proteins encoded by MSH2 and MLH1 genes repair errors made during DNA replication When these genes are inactivated by mutation,

microsatellite mutation rates increase, promoting mutations in other genes

Chromosome Rearrangements and Cancers

Some cancers, such as chronic myelogenous leukemia, are caused by translocation events, creating hybrid genes that activate cell division Philadelphia chromosome - was first discovered and described in 1960

by Peter Nowell from the University of Pennsylvania School of Medicine and David Hungerford from the Fox Chase Cancer Center's Institute for Cancer Research and was therefore named after the city in which both facilities are located.

The Philadelphia Chromosome

Abnormal chromosome produced by translocation between the long arms of chromosomes 9 and 22 Linked to chronic myelogenous leukemia (CML)

Translocations and Hybrid Genes

Many proto-oncogenes are located at or close to the breakpoints of chromosomal translocations involved with specific forms of leukemia

In chronic myelogenous leukemia, the C-ABL gene (chromosome 9) is moved next to the BCR gene (chromosome 22) The hybrid gene encodes an abnormal protein

that signals CML cells to divide

Translocations Associated with Cancers

Genomics, Epigenetics and Cancer

Sequencing cancer genomes has allowed the identification of additional cancer-associated genes

VIDEO: Genetically Modified Virus Used to Fight Cancer

VIDEO: Genome Research Improving Cancer Understanding

Breast Cancer Susceptibility Genes

Epigenetics and Cancer

Abnormal DNA methylation is associated with many types of cancers

Epigenetic changes to DNA can alter gene expression and contribute to cancer

Epigenetics and Cancer

Chromatin

Chromosome Epigenetic factors (methyl groups, acetyl groups, phosphate groups)

DNA methylation Methyl group can

tag DNA and activate or

repress genes.

Histone tails

Methyl group Histone modification The

binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the accessibility of genes in the DNA.

DNA Gene

Histones are proteins around which DNA can wind for compaction and gene regulation

Histone DNA accessible, gene active

DNA inaccessible, gene inactive

Targeted Therapies

Use drugs that selectively block the activity of specific oncogenes Gleevec blocks the BCR-Abl oncogene in CML Herceptin blocks the HER2 receptor on certain

breast cancers

Targeted Therapies ATP P P P

BCR–ABL hybrid protein

Signal protein

(a)

P

Signal protein

CML

Targeted Therapies

Gleevec

BCR–ABL hybrid protein

Signal protein

(b)

No CML

Cancer and the Environment

Many cancers are environmentally induced Epidemiology

The study of factors that control the presence, absence, or frequency of a disease

Provides statistical correlation between the environment and diseases such as cancer

Rate of Melanoma22.5

20

17.5

15

12.5

10

Rat

e pe

r 100

,000

7.5 KEY

5 Male and femaleMale

2.5 Female

0

19821998

19992000

Year of diagnosis1973

19741975

19761977

19781979

19801981

19971996

19951994

19931992

19911990

19891988

19871986

19851984

1983

Cancer and Environmental Factors

Smoking: 85% of lung cancer in men and 75% in women are related to smoking

Sunlight and skin cancer Some viral infections: HPV and cervical cancer Radiation Occupational exposure to some chemicals

Types of Skin Cancers

Basal-cell carcinoma

Squamous-cell carcinoma

Malignant melanoma

The Genetic Revolution: Cancer Stem Cells

A new cancer model states that some cancers have stem cells

A small population of cells in the tumor whose continuous division drives the growth of the tumor

May offer a new more specific approach to therapy

1. What are the ultimate cause of cancer?2. What is a somatic cell?3. What are 5 causes of cancer (On Cancer and Genetics slide)?4. What is a tumor suppressor gene?5. What is a proto-oncogene?6. What are the two types of retinoblastoma?7. What are the two mutations that predispose women to breast

and ovarian cancer?8. What is familial adenomatous polyposis?9. What disease is the Philadelphia chromosome linked to?10. What is epidemiology?11. What percentage of lung cancer in caused by smoking in

men? In women?