Genetics plays a key role in cancer development. Cancer results from mutations in proto-oncogenes, tumor suppressor genes, miRNA genes, and mutator genes. Proto-oncogenes promote cell growth but become oncogenes when mutated. Tumor suppressor genes normally inhibit cell growth but are inactivated by mutations in cancer. The cell cycle is tightly regulated by checkpoints but deregulation can lead to uncontrolled cell division in cancer. Cancers can be caused by inherited genetic mutations or environmental exposures like radiation and carcinogens. The development of cancer typically involves multiple genetic alterations accumulating over time.
2. Genetics controls cell division and tissue
differentiation
Proliferation is tightly controlled
Cell transformation results in unregulated
growth (oncogenesis)
Benign growth is restricted to one site
and is readily managed.
Malignant growth is metastatic – it
spreads throughout the body.
3. Relationship of the Cell Cycle to Cancer
Cell differentiation occurs as cells proliferate to form
specialized tissues. Differentiated cells lose the ability to
proliferate and have a finite life span
Cell proliferation is executed by the cell cycle, which is
divided into 4 phases
G1 (gap 1), S (synthesis), G2 (gap 2), M (mitosis)
The cell cycle is controlled by gene-activity driven
checkpoints, which arise due to DNA damage***
The G1-to-S checkpoint monitors cell size
The G2-to-M checkpoint monitors the cellular environment and
the status of DNA duplication
Checkpoints use cyclins and cyclin-dependent kinases
Kinase phosphorylation of the cyclin can activate or cancel cell
cycle progression
4.
5. The regulation of cell division is controlled by extracellular and
intracellular means (signal transduction pathways) that stimulate or
inhibit growth (obviously, these pathways are altered in cancer)
Animation: CellAnimation: Cell
Division RegulationDivision Regulation
6. Cancers are Genetic Diseases
There is strong evidence supporting the notion that
cancer is a genetic disorder:
Some cancers are familial (hereditary), while others
are sporadic (nonhereditary)
In general, cancer is not inherited (mutations are in
somatic, not germ line cells)
Some viruses can induce cancer, indicating the action
of viral genes
Descendants of cancerous cells are all cancerous
Cancer risk rises with exposure to mutagenic agents
Specific chromosomal mutations are associated with
certain kinds of cancer
7. Four classes of genes are mutated in cancer:
Proto-oncogenes, whose products normally
stimulate cell proliferation (c-onc, v-onc)
Tumor suppressor genes, whose products
normally inhibit proliferation
Micro RNA (miRNA) genes, which produce
small RNAs that silence the expression of
other genes
Mutator genes, whose products ensure
accurate replication and maintenance of the
genome
Genes and Cancer
8. Oncogenes
Tumor viruses induce infected cells to
proliferate and produce a tumor
There are two types based on the viral
genome:
RNA tumor viruses transform cells by
inducing viral oncogenes (genes
causing unregulated proliferation)
DNA tumor viruses do not carry
oncogenes and use other mechanisms
to transform the cell
9. Retroviruses and Oncogenes
RNA tumor viruses are all retroviruses, and their
oncogenes are altered forms of normal host
genes(Not all retroviruses are oncogenic)
Structurally, retroviruses have two copies of a
10-kb ssRNA genome, encoding genes for:
The gag group antigen, which encodes the
viral protein core (capsid)
The pol gene, which produces reverse
transcriptase and integrase
The env gene, which encodes the infectious
surface glycoprotein
10.
11. Upon infection, the ssRNA
genome is released from
the virus and reverse
transcribed to ds DNA
(proviral DNA) by reverse
transcriptase (RNA-
dependent DNA pol)
Proviral DNA integrates
into the host chromosome,
controlled by viral
elements encoded in their
LTR’s
Host RNA polymerase II
transcribes the proviral
DNA and viral mRNAs are
produced by alternative
splicing
12. Viral Oncogenes
Oncogenic retroviruses carry an oncogene that is not
involved in the viral life cycle (different retroviruses
carry different oncogenes and thus, different cancer)
Retroviruses that carry an oncogene are transducing
and are formed by the random integration of the
provirus into the host chromosome
13. Cellular Proto-Oncogenes
Cellular proto-oncogenes with close homology to v-
onc have been characterized, showing that:
Oncogenes are present in human tumor cells and
cause transformation when introduced into normal
cultured cells
Human cells have intron-containing genes that are
very similar to viral genes (no introns***), but do
not cause cancer (proto-oncogenes)
These genes regulate cell division and
differentiation, and can be mutated to cause
cellular transformation (dominant mutation)
15. Normal Transformed
PDGF driven transformation in fibroblasts
No contact inhibition produces
altered histology (round shape)
16. Changing Proto-Oncogenes into Oncogenes
Conversion of proto-oncogenes to oncogenes
relaxes cell control, allowing unregulated
proliferation
Point mutations in coding or controlling
sequences changes the gene product or alters
its expression (i.e. Ras)
Deletions of coding or controlling sequences
changes the amount of activity of growth
stimulatory proteins (i.e. Myc)
Gene amplification, caused by random
overreplication of regions of genomic DNA,
increases the amount of stimulatory proteins
17. DNA Tumor Viruses
Oncogenic DNA viruses do not carry oncogenes
but may transform cells using viral gene
products
DNA viruses induce the production of cellular
DNA replication enzymes, which are used in
viral replication
Very rarely, viral DNA integrates into the host
genome, producing proteins that stimulate the
cell to proliferate (HPV is an example)
18. Tumor Suppressor Genes
In a pioneering experiment, Henry Harris showed the fusion
of cancer cells and normal cells does not always result in a
tumor, indicating the existence of tumor suppressor genes
In certain cancers, both homologous chromosomes show
deletion of specific regions which are the sites of tumor
suppressor genes (so these mutations are recessive)
19. Retinoblastoma Tumor Suppressor, RB
Retinoblastoma is the most
common eye tumor in
children; surgery and
radiation is effective (90%)
Retinoblastoma has two
forms:
Unilateral, sporadic
retinoblastoma develops in
children with no family history
Bilateral, hereditary
retinoblastoma is the
paradigm of Alfred Knudson’s
two-hit mutation model,
stating two mutations are
required for RB development
21. Retinoblastoma is rare among cancers because a single gene
is critical for its development (most cancers result from a series
of mutations in different genes; discuss later)
pRB regulates the cell cycle at the G1-to-S checkpoint
pRB is ~P by CyclinE/Cdk2; E2F is free to transactivate DNA
Some DNA tumor viruses produce proteins sequestering pRB
22. TP53 Tumor Suppressor Gene
The tumor suppressor p53 is
found mutated in roughly 50%
of human cancers!
Inheritance of one mutant p53
allele results in the Li-Fraumeni
syndrome, in which a rare form
of cancer develops in several
tissues
Tumors arise when the 2nd
allele is mutated, so the trait is
inherited as autosomal
dominant
The figure tells the story
~P
Animation: TumorAnimation: Tumor
Suppression (p53)Suppression (p53)
23. P53 provides
protection from
oncogene activation
Oncogenes induce
ARF expression,
producing p14
P14 binds Mdm2,
stabilizing p53
concentration
P53 transactivates
target genes involved
in arrest, apoptosis
and repair
Note: DNA damage
by radiation or chemo
is used to study p53
25. BRCA1/2
Mutation in breast cancer
tumor suppressor genes
are similar to pRB;
hereditary forms produce
early onset, bilateral
tumors
Mutations in BRCA1 are
also involved in the
genesis of ovarian cancer
Surprise District Court Ruling
Invalidates Myriad Genetics’
BRCA Patents; sequence
data is not patent domain.
“can man patent the sun?” –
Dr. Jonas Salk (Polio
vaccine)
26.
27.
28. MicroRNA and Mutator Genes
MicroRNAS are short, noncoding ssRNAs derived from the
transcripts of nuclear genes. They silence mRNA translation by
binding to the 3’ UTR
Many miRNAs show altered expression patterns in cancer cells.
miR-155 miRNA is overexpressed in lymphoma and breast, lung, and thyroid
cancer. When expression of an miRNA is increased in cancer cells, it is
considered an oncogene
let-7 miRNA is underexpressed in breast, liver, lung, and thyroid cancer. When
expression of an miRNA is decreased in cancer cells, it is considered a tumor
suppressor
A gene that increases the spontaneous mutation rate when it is
mutated is a mutator gene (DNA replication and repair genes)
Hereditary nonpolyposis colon cancer results from an autosomal dominant allele,
causing early onset of colorectal cancer (mutations in hMSH2, hMLH1, hPMS1
and hPMS2)
29. Telomere Shortening, Telomerase & Cancer
Telomere shortening and telomerase activity are related
to the development of human cancer
Human cells undergo replicative senescence caused by
structural changes in the telomeres
Only germ-line and certain stem cells maintain telomerase
activity
Telomeres of other cells shorten with each cell cycle.
Eventually, telomeres are so small, the telomere-binding
proteins are unable to bind to the shortened telomeres. The
lack of binding results in DNA damage and cell cycle arrest
If the cell is mutated in a cell cycle arrest gene (e.g., TP53),
the cell will divide despite having short telomeres. In
addition, if the telomerase gene is reactivated, the cells can
become immortal (do you think cancer cells have mutations
in both of these genes at the same time?)
30. Multistep Nature of Cancer
Cancer induction may
require the accumulation
of many mutations over
time, involving
oncogenes and tumor
suppressors
The paradigm of the
multistep nature of
cancer is embodied in the
intestinal cancer,
adenamatous polyposis
(FAP)
31. Chemicals and Radiation as Carcinogens
Chemical carcinogens are divided into two major classes
(both types of carcinogens cause point mutations):
Direct-acting carcinogens bind DNA and act as mutagens. Alkylating
agents are an example
Procarcinogens are metabolically converted by normal cellular enzymes
to ultimate carcinogens that bind DNA and cause mutations. Most
chemical carcinogens are procarcinogens. Examples include:
Polycyclic aromatic hydrocarbons are found in smoke from wood, coal, and
cigarettes
Azo dyes, natural metabolites (e.g., aflatoxin from fungi)
Nitrosamines (from nitrites in food)
Only about 2% of cancer deaths are caused by
radiation, but the cancers are often highly aggressive
melanomas. Sources include:
Sun (U-V), X-rays, cellular telephones, Radon gas
Ionizing radiation (from X-rays, radioactive materials, and radon gas) can
cause leukemia and thyroid cancer