Cancer

CHAPTER 22Genetics of Cancer

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.

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

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: Cell Animation: Cell Division RegulationDivision Regulation

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

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

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

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

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

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

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)

Proto-Oncogene Proteins Proto-oncogenes fall into many

classes with characteristic protein products, all of which stimulate cell growth

Normal Transformed

PDGF driven transformation in fibroblasts

No contact inhibition producesaltered histology (round shape)

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

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)

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)

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

L.O.H.

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

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: TumorSuppression (p53)Suppression (p53)

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

…another look at the intimate couples

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)

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)

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?)

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)

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