Cancer: Driver Mutations and Categories

• Cancer arises from a single mutated cell that gives rise to a subpopulation of mutated cells, progressing to a malignant phenotype over years.

Driver vs. Passenger Mutations

• Driver mutations confer growth or survival advantages and amount to a small part of total mutations.
• Passenger mutations are biologically inert and do not contribute to tumor development.

Cancer Categories

• Carcinomas are cancers that arise from epithelial cells (90% of malignant tumors). Examples include lung, prostate, breast, skin, and colon cancers.
• Sarcomas are rare cancers originating in supporting tissues (~1% of malignant cancers). Examples: blood vessels, adipose, muscle, and bone cancers.
• Lymphomas/leukemias arise from lymphatic and blood cells. Lymphoma: solid mass of white blood cells. Leukemia: malignant blood cells proliferate in the bloodstream.

Cell Cycle Targets

• Mutations in pre-malignant tumor cells fall into two main categories, inactivated tumor suppressors and oncogenes.
• Inactivated tumor suppressors cannot restrain the cell cycle during DNA damage or repair DNA when damaged. Examples: p53, Rb, p21, p16.
• Oncogenes abnormally stimulate cell proliferation, increasing cyclin D and cycling. Examples: Ras, Myc.
• Malignant cells result from a combination of oncogenes and inactivated tumor suppressor genes.

Tumor Development Stages

Initiation Stage

• A cell receives a mutation, becoming capable of abnormal growth.

Promotion Phase

• An initiated cell is stimulated to grow by external factors like growth factors or inflammation.
• This stage is reversible if the external growth factor is no longer there.

Progression Phase

• The cell accumulates enough mutations to proliferate on its own, without external factors.

Cancer Genomes

Germline Genome

• Familial cancer syndromes typically result from the transmission of a single mutated tumor suppressor gene.
• Additional mutations are required for tumors to develop.

Tumor Genome

• Contains multiple mutations that accumulate in a tissue over time.

• Some mutations (TP53, RB, RAS, MYC) are frequently found, whether or not a germline mutation is present.

• Somatic genome in familial cancer syndromes: all body cells carry the mutation, predisposing the individual to cancers.

• Tumor genome is tissue specific, with mutations arising in only one location and varying between tumors from the same person.

Genetic Factors: Tumor Suppressor Genes

RB

• Normal Role: Restriction point control.
• Familial Cancer Syndrome: Retinoblastoma.

TP53

• Normal Role: DNA damage/apoptosis.
• Familial Cancer Syndrome: Li-Fraumeni.

APC

• Normal Role: Prevents growth signaling in the upper colon crypt.
• Familial Cancer Syndrome: Familial adenomatous polyposis (FAP).

NF1

• Normal Role: Inhibits RAS signaling.
• Familial Cancer Syndrome: Neurofibromatosis type I.

BRCA1, BRCA2

• Normal Role: DNA break repair.
• Familial Cancer Syndrome: Familial Breast Cancer.

MSH2, MLH1

• Normal Role: DNA mismatch repair.
• Familial Cancer Syndrome: Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome).

XP Genes

• Normal Role: Pyrimidine dimer repair.
• Familial Cancer Syndrome: Xeroderma Pigmentosa.

Tumor Suppressors p16 and p21

• The cell cycle is subject to interruption through the action of cyclin-dependent kinase inhibitors p16 and p21.
• p21 protein can halt the cell cycle at any phase when there is DNA damage.
• p16 protein can halt the cell cycle by interfering with cyclin D-CDK4/6 activity.
• This prevents proliferation in the absence of inappropriate growth signals.
• Mutations that inactivate these proteins are frequently found in human cancers.

Tumor Suppressors: The Loss of Good Genes

• Cells have two copies of a gene and maintain tumor suppressor function until both gene copies are inactivated (the loss).
• Cells that suffer a "loss of heterozygosity" in a tumor suppressor lost their last fully functioning gene.
• P16, P21,and Rb are tumor suppressors for for which fully functioning genes typically need to be lost.
• TP53 is an exception to tumor suppressors generally needing the loss of both fully functioning genes.

p53: Guardian of the Genome

• TP53 codes for the p53 protein, originally identified in 1979 and thought to be an oncogene.
• TP53 is mutated in 50% of human tumors
• p53 protects cells from DNA damage by allowing time for repair.
• p53 protects tissues from DNA damage by inducing apoptosis (preserving the normal cell population).

DNA Damage and Cycling

• When there is DNA damage, transcription factor p53 levels are increased.
• p53 binds to the promoter region of the p21 gene, increasing p21 mRNA synthesis.
• p21 protein can bind to CDK/cyclin complexes, inhibiting their activity (except CDK4/6-cyclin D).
• Cell cannot pass through the restriction point because Rb cannot be phosphorylated by CDK2-cyclinE.

Dealing with Irreparable Damage

• P53 mediates a different cellular response when DNA is damaged beyond repair.
• Phosphorylated p53 stimulates the transcription of the gene PUMA (p53-upregulated modulator of apoptosis).
• Increased levels of PUMA protein causes the cells to commit suicide, and mutated cells are destroyed so they cannot be passed to daughter cells.

Li-Fraumeni Syndrome

• A hereditary defect in the p53 gene.
• Individuals have a 90% chance of developing cancer.
• Incidence of li-fraumeni Syndrom is rare, only a few hundred families have been diagnosed with the condition worldwide.

The Morphology of Apoptosis

• Apoptosis is how the body eliminates damaged cells.
• Apoptotic cells disintegrate into membrane-bound components (apoptotic bodies) phagocytized by cells to remove them.
• This keeps toxic components of the cytoplasm contained.

Retinoblastoma: Mutation of the Tumor Suppressor Rb

• The Rb protein controls the restriction checkpoint in G1.
• It's a potent tumor suppressor, and the mutation of both RB gene copies can lead to retinoblastoma.
• The RB mutation affects the retina, with possibility of affecting one or both eyes.
• Retinoblastoma is the most common neoplasm of the eye in childhood (3% of pediatric cancers).
• Immature human retinal cells are highly proliferative and at high risk for DNA damage,

Rb Loss Consequences

• Rb loss has two consequences: E2F is unrestrained, so mutated cells proliferate without growth signal.
• Cell cycle inhibitors cannot halt the cell cycle, meaning there is no time provided to repair.

Knudson's "Two-Hit" Hypothesis

• In 1971, Alfred Knudson proposed the model of retinoblastoma saying mutations of both RB copies in a cell are required.
• Loss-of-function mutation typically sustains the RB gene, meaning, at a cellular level, even one good copy is sufficient to halt the cell cycle.
• Losses of one normal RB gene predisposes humans to lose copies (phenomena). Only one inherited mutation is sufficient.

Familial Adenomatous Polyposis

• A heritable mutation in the APC gene causes an autosomal dominant familial cancer syndrome called familial adenomatous polyposis (FAP).
• FAP patients develop hundreds or thousands of colorectal polyps (adenomas) early in life.
• This is almost certain to progress to carcinoma by age 40. The individual will develop colorectal cancer if the colon is not removed.

Neurofibromatosis

• Neurofibromatosis type 1 is an autosomal dominant cancer syndrome through mutation of the NF1 gene (neurofibromin protein)
• Results in many benign tumors (neurofibromas) on nerve tissue. Neurofibromatosis is defined by this.
• Café au lait spots, skin hyperpigmentation, and lisch nodules (lesions iris) are common symptoms.

Neurofibromin Decreases Ras Activation

• GTPase RAS is responsible for the auto-shutoff signaling, but neurofibromin's product, NF1, is to decrease Ras activation.
• Activation is decreased by causing Ras to hydrolyze and adopt an inactive form quickly.
• Ras has greater activity and increases cell division when neurofibromin is lost or mutated.

BRCA1 and BRCA2 genes

• BRCA1 and BRCA2 DNA repair proteins participate in homologous recombination.
• Homologous recombination is the highest quality method for double-stranded DNA Breaks.
• Mutations found here account for 10% of breast cancers.
• BRCA1/BRCA1 mutations by themselves do not drive cell proliferation.
• Instead, the mutation decreases likelihood of repair.

Hereditary Non-polyposis Colon Cancer (HNPCC)

• Hereditary non-polyposis colon cancer (HNPCC) is also termed Lynch syndrome; a familial cancer that is 2%-3% of all colon cancers.
• It is autosomal, meaning 90% of individuals will develop.
• Causes multiple gene mutations in mismatch repair and includes MSH2 (60% cases), MLH1 (30% cases).
• DNA progression takes 2-3 years vs not having it at 8-10 years

Xeroderma Pigmentosum

• Xeroderma Pigmentosum is an autosomal recessive disorder characterized by defects in the nucleotide excision repair pathway.
• Pyrimidine dimers that form upon sunlight, which requires repair via the pathway, leads to individuals feeling intolerant of sunlight.
• XP patients have greater risk of developing skin cancer and squamous carcinoma of the tongue.
• Skin cancers develop in children by age 8, 50 for non-XP adults..

Cancer Genome Categories

• The genomes with cancer are put in the categories of patient's germline genome and tumor genome.
• As also noted with L7 of the study guide.

Germline Mutation

• Familial cancer syndromes come from a single mutated tumor suppressor gene.
• Examples include oncogenes/tumor suppressors from one transmission.

Multiple Mutation

• The tumor genome is itself the multiple mutation, in that multiple mutations accumulate over time in tissue.

• These can occur with or without the germline and can be individual.

• Somatic genome in familial cancer syndromes: all body cells carry the mutation, predisposing the individual to cancers.

• Tumor genome is tissue specific, with mutations arising in only one location and varying between tumors from the same person.

In Conclusion

• Proto-oncogenes code for non-mutated proteins naturally.
• Proto-oncogenes are are a key part of cell survival when regulated correctly
• However, proto-oncogenes can be mutated that causes cell activity or is expressed at abnormal levels.
• The mutations are gain-of-function, therefore only a single mutated gene can stimulate cell growth.

Oncogene vs. Mutations in Actives

Mutations

• Tumor formation includes suppressor genes inactivated, caused from losing a function.
• Tumors are defined here are homozygous gene defined at 2 normal copies, but over a loss, that gene is expressed but not functioning,
• The loss causes hetero gene and one mutated copy.

Oncogennes

• mutations are defined at gaining function.
• However, proto-oncogenes here includes gain-of-function but the function is a mutation or loss therefore.
• The difference between two definitions comes from its function or how proto-oncogenes act.

Oncogenes & Cell Cycling

• Signals from protein with cyclin D are a mutation, in that certain cases causes abnormal growth
• But that abnormal growth does have a way to stop it unless there is sustained inactivation of tumor suppressor.
• A well as noted with how that applies to all, with the RAS protein is one of the abnormal pathways.
• The abnormal amount of protein is one that does not have mutation.

Proto-oncogenes and Disease

Protein RAS

• This protein is signaled when bound at GTP, and it Hydrolyzes GTP to shut off signaling.
• A proto form of Ras is called RAS.
• Mutations here usually relate to having an inability to cut GTP.

MCV Gene

• Protein that stimulates transciption of cyclin D and 15% other genes.
• Has two mutations defined.

Burkitt Lymphoma

• Requires a chromosome translocated and can be treated with Riturimab .
• It cannot function at ABL

ABL

• Enocodes a tyrosine kinase.
• The ABL encodement that the tyrosine kinase is at growth signaling, forming philadelphia chromosome,
• In which the BCR has a tyosine kinase activity vs ABL gene, to where it can be treated.
• Can also be referred to as Gleevec (imatinib).

Overexpression of MYC Genes

MYC

• The transcription and a mount is a normal transciption.

Burkitts

• The promoter becomes highly active and a single copy is generated.

Mutation of MYC

• The Myc gene will activate expression of 15% of the known genes in cell growth, the oncogenes is human tumor
• The protein is syenthiszed after genetic alteration but one that can also becomes amplified, creating 150 copies per cell.
• And rearrangement is transcription of gene promoted by MYC .

Ras Mutation & Point Mutations

• Ras will eventually be simulated and released with binding, and has activation with kinases.
• In a normal state the GTP will result in that signal stopping in cell cycle.

Proto-oncogene

• Tumors have 1/3 mutation. But a mutation will cause turn-off if there is no stimulation from ligand.
• Also has signal growth even after if there is active ligand.

Rituximab

• Causes cell malfunction and overweight. Therefore, it is B-cell induced because the tranmembrane is linked
• Transmembrane is linked to CD20 where found on surface of B, and causes destructions from: apoptosis, lyse, or immune system

Angiogenesis

• Eventually the tumor will become oxygen and nutrient starved, requiring growth factors with blood vessels. Here are the supports that comes from Anagiogenis:
  1. Oxygen provides.
  2. Nutrients provide.
  3. Access to circulation (metastasis).

How is it done?

1. Cell has to come and invade the tissue for vessel production.
2. Cancer also includes the transported system because is where the cell is stored
3. However, in cell level there has to be tumor relocation for location changing.

Metastatic Sites

• Colonization will depend on the factors in tumor and tissue, so the metastatic sites can come a advantage during cell change.
• This applies into areas known as seed and soil-type because they are compatible together.
• Although, there may be picky types that cell has during their new homes.

Carcinogens & Cancer

• Most of the studies suggests environment, compared to those which have heredity issues
• Even if physical aspect is included, also counts social, culture which affect lifestyle
• Here are list a that cause cancer: viruses, diet ,tobacco and alcohol, obesity

Alcohol vs. Tobacco

• The risk of developing some cancer is higher because with that, it is damaged via carcinogens,
• Although cell can start to repair, some cannot and causes even higher issue.
• Known "Heavy drinking" means there are 30 drinks per week that damages person, a great risk for one.
• “Heavy” smoke=2 packs/day or 20 years, it takes a single day before that smoke harms a person.

Obesity

• Study suggests that the correlation shows rise to having mass of the cancer even after period.
• Diabetes will also have rise and may even give tumor devlopment the signals ( inflammatory signalling even)
• Increase the tumor and the number of initiated cells.

Excercise

• Lowers the risk of cancer and if they follow they can have lower counter parts in lifestyle.
• Also the biggest factor that helps is with active lifestyle even if body is still large, therefore lower risk due to activity.