The Genetics of Cancer Genetics Spring 2016

Today we will cover.... 18.1- Cancer is genetic but usually not inherited From single mutations to sweeping changes in gene expression Loss of cell cycle control Inherited vs. Sporadic cancer 18.2 Characteristics of cancer cells

Cancer is genetic but not usually inherited Tumor A growth formed in solid tissue Occurs when a cell loses control on division rate May be benign or malignant

Cancer is genetic but not usually inherited Benign A tumor that grows in place (not cancerous) Does not spread into surrounding tissue

Cancer is genetic but not usually inherited Malignant Tumor that infiltrates nearby tissues (cancerous) Also sends parts of itself into a transport system Ex. the bloodstream or lymphatic vessels Process is called Metastasis

Cancer is genetic but not usually inherited Cancer- a group of disorders that arise from alterations in genes 10% of cases are inherited as single-gene disorders Mutations are in every cell 90% of mutations occur in a few somatic cells over a lifetime

Cancer is genetic but not usually inherited Cancer is a genetic disease at the cellular level Mutations in genes are occurring Cancer is NOT usually a genetic disease at the whole body level I.e. it is not usually inherited from a parent

Cancer is genetic but not usually inherited Why does cancer seem to run in families? Combinations of particular gene variants sum to increase the risk Cancer does not follow a Mendelian pattern of inheritance Takes years to develop

Single mutations to sweeping changes Research identified genes that cause cancer More than 100 oncogenes More than 30 tumor suppressor genes

Single mutations to sweeping changes Oncogenes Cause cancer when they are inappropriately activated Tumor Suppressor Genes Cause cancer when they are deleted or inactivated

Before we move on... Let's review the cell cycle

Loss of cell cycle control Cancer is a consequence of cell cycle disruption Begins when a cell divides more frequently than the normal cell type it came from

Loss of cell cycle control The cell cycle is under genetic control However, cells go through this cycle so often they can at times lose control The immune system destroys most cancer cells Recognizes tumor-specific antigens on the cell surface

Loss of cell cycle control How can cells lose control? Mutation in a gene that normally halts or slows the cell cycle Leads to inappropriate mitosis By not stopping or slowing down, there is not enough time to repair DNA Leads to mutations in oncogenes and/or tumor suppressor genes

Loss of cell cycle control Loss of telomere length may also contribute to cancer Telomere- tips of chromosomes that protect them from breaking Consists of the DNA sequence TTAGGG repeated thousands of times

Loss of cell cycle control As cells divide and become more specialized, it is normal for them to lose telomere length Ex. Skin cells, nerve cells, muscle cells

Loss of cell cycle control Other cells must maintain telomere length Ex. Sperm cells, oocytes These will make a new organism so they need to be able to divide a lot

Loss of cell cycle control Telomeres can maintain length due to an enzyme called “telomerase” In specialized cells, telomerase is turned off Signals the cell to stop division when cell reaches proper size

Loss of cell cycle control In cancer cells, telomerase is turned back on Causes cells to continue dividing Uncontrolled division causes a tumor to form, grow and spread

Inherited Vs. Sporadic Cancer Somatic Mutation Somatic means nonsex cells Sporadic cancer arises from mutations in these cells NOT directly passed on to future generations Gametes do not carry the mutant alleles

Inherited Vs. Sporadic Cancer Germline Mutations Germline means gametes (sex cells) Mutant alleles ARE passed on because they are in every cell, including gametes Inherited cancer occurs when a second mutation occurs in a somatic cell

Inherited Vs. Sporadic Cancer Heavy smokers Lung cancer requires two mutations in the oncogenes or tumor suppressors Smokers who have one inherited mutation are more susceptible

Inherited Vs. Sporadic Cancer Heavy Smokers Cancer can still arise without an inherited mutation BUT It is less likely Takes more time for two mutations to occur rather than one

18.2 Characteristics of Cancer Cells Cancer cells look different More rounded b/c they do not adhere to surrounding normal cells as strong Plasma membrane is more fluid Cell surface may have different antigens OR it may have the same antigens, just a different number of them

Characteristics of Cancer Cells When a cancer cell divides, both daughter cells are cancerous Cancer is also transplantable

Characteristics of Cancer Cells Dedifferentiated​ Less specialized than normal cells​ Ex. Skin cancer cell​ Rounder and softer​ More like a stem cell

Characteristics of Cancer Cells Cancer cell growth is unusual​ Normal cells grow in a single layer​ Cancer cells pile up on each other​ Produces tumor​ Lack contact inhibition​ Do not stop dividing when crowded

Characteristics of Cancer Cells Invasiveness​ Surface structure allows them to squeeze into any space​ Secrete enzymes to cut paths through healthy tissues​ Invasive malignant tumors​ Grows irregularly​ Sends "tentacles" in all directions

Characteristics of Cancer Cells Angiogenesis​ Growth of new blood capillaries ​ Cancer cells stimulate this growth when they reach a new site​ New capillaries supply the tumor with nutrients and remove waste

Characteristics of Cancer Cells Metastasis​ When cancer metastasizes, new tumor cells often mutate more​ Causes chromosomes to break or rearrange​ Cancer cells become anuploid​ New genetic entity​ May resist treatments that were effective on original tumor

Characteristics of Cancer Cells On the bright side​ Gene expression patterns associated with metastasis can be detected early on​ New cancer treatments may prevent metastasis

18.3 Origin of Cancer Cells Most cancer cells are More specialized than stem cells Less specialized that cells in nearby tissue

Origin of Cancer Cells Which cell type does cancer come from? Descend from a stem cell? OR arise from a specialized cell?

Origin of Cancer Cells Actually, it can happen either way But the pathways to get cancer are different

Origin of Cancer Cells Cancer stem cells Produce cancer cells Also produce abnormal specialized cells Found in cancers of the brain, blood and epithelium Epithelium = breast, colon and prostate cancers

Origin of Cancer Cells Specialized cells may lose some of their characteristics May be caused by mutations during division OR cells may begin to express “stemness” genes These override signals to differentiate

Origin of Cancer Cells Another possible origin is loss of balance in the tissues Normal tissue may be 5% stem cells, 10% progenitor cells and 85% differentiated cells Mutations may create higher percentages of stem and progenitor cells Extra cells form tumor

Origin of Cancer Cells Uncontrolled tissue repair If tissue is injured, cells divide to replace lost ones If too many cells continue to divide to fill the void, tumor forms

18.4 Oncogenes Proto-oncogenes are normal and regulate cell division Function as oncogenes when activated at the wrong time or place When proto-oncogenes translocate, they may increase expression New location may also cause a new protein to form Ex. Fusion Protein Oncogenes may create too many proteins Ex. Her-2/neu

18.4 Tumor Suppressors Normally suppress tumor formation Response to growth inhibiting signals Mutations or deletions of these genes can cause cancer Ex. Retinoblastoma (RB), p53 and BRCA1

Retinoblastoma Malfunctions cause eye tumor Mutations can be inherited A second somatic mutation causes tumor to form Usually earlier onset Mutations can be sporadic Two somatic mutations cause a tumor to form Usually later onset

p53 Normally “decides” if a cell should repair DNA errors or die Loss of this gene causes cells to continually divide without DNA repair P53 mutations typically occur only in somatic cells In rare cases, the mutation can be inherited Gives a very high risk of developing cancer

BRCA1 Inherited breast cancer is usually caused by mutations in BRCA1 and BRCA2 genes Both genes encode for similar proteins that function in controlling the cell cycle BRCA2 encodes for a larger protein with more functions

18.5 A Series of Genetic Changes causes Some Cancers Certain single genes set the stage for cancer​ Mutations cause chromosomal instability​ Ex. BUB1B- cause aneuploidy​ About ¼ of a person's cells have missing or extra chromosomes​ Causes various childhood cancers

A Series of Genetic Changes causes Some Cancers Two categories of "stage setting" cancer genes​ Gatekeepers​ Control mitosis and apoptosis​ Caretakers​ Control mutation rates of gatekeepers

A Series of Genetic Changes causes Some Cancers As cancer progresses, more genetic changes accumulate​ We study cancer at various stages​ Allows us to identify mutant genes that are present early on​ We can also find potential points of treatment

A Series of Genetic Changes causes Some Cancers Two types of cancer that arise from a series of changes in gatekeeper and caretaker genes​ Rapidly growing brain tumor​ Colon cancer

Brain Tumor Astrocytomas​ Tumor that grow in astrocytes​ Astrocytes connect neurons to blood vessels​ Development and progression of this cancer has 4 major genetic changes

Brain Tumor 1. loss or mutation of BOTH p53 alleles​ 2. loss of several genes on BOTH copies of chromosome 9​ Interferons ​ Tumor suppressor genes​ 3. activation of oncogene on chromosome 7​ 4. Loss of one or both copies of chromosome 10

Colon Cancer 5% of colon cancer cases are inherited​ People with cancer have family members with non-cancerous growths (polyps)​ 1 in 5,000 have these precancerous polyps​ Called Familial Adenomatous Polyposis 

Colon Cancer Polyposis begins in early childhood​ Hundreds of tiny polyps develop and progress to cancer over many years​ Colon lining cells usually only live 3 days​ W/ polyposis they don't die and build up to form polyps

Colon Cancer Development of cancer from polyps begins with deletion of the APC gene​ APC is the main gatekeeper gene for colon cancer​ It's protein helps control mitosis​ When protein is not there, mitosis is continually activated

18.6 Environmental Causes of Cancer 6 types of cancer appear to be inherited Prostate Stomach Lung Colon Kidney bladder

Environmental Causes of Cancer However, 3 of these also appear to have environmental influences Stomach Colon lung

Environmental Causes of Cancer Environmental factors can include: Diet Pollution and smoke Excessive sun exposure

Environmental Causes of Cancer Chemoprevention- an active approach to minimize environmental influences Chemopreventatives include Folic acid Vitamins D and E Anti-inflammatory drugs

Considering Carcinogens Eating cruciferous vegetables activates “xenobiotic metabolizing enzymes” Veggies such as broccoli and Brussel sprouts These enzymes break down heterocyclic aromatic amines Carcinogenic products of cooked meat Cause mutations associated with colon cancer

Methods to study cancer-environment links Population Study Compares the incidence of a type of cancer among many different groups of people These studies often have too many variables to establish cause and effect

Methods to study cancer-environment links Case-control Study People with cancer are matched with healthy individuals for characteristics Such as age and gender Researchers then look for differences

Methods to study cancer-environment links Prospective study Most informative type of study Two or more groups of people follow a specified activity plan Dietary regimen Check ups for cancer

18.7 Human Genome Data Tailor Diagnosis and Treatment Treatments for cancer include:​ Surgery​ Radiation and Chemotherapy​ Alternative Drug Therapies

Human Genome Data Tailor Diagnosis and Treatment Surgery ​ Oldest cancer treatment​ Prevents invasiveness by removing the tumor

Human Genome Data Tailor Diagnosis and Treatment Radiation and Chemotherapy​ Kill all cells that divide rapidly​ Also affects healthy cells​ Patients receive other drugs to manage side effects

Human Genome Data Tailor Diagnosis and Treatment Alternative Drug Therapies​ Stimulate cells to regain specialized characteristics​ Inhibit telomerase​ Angiogenesis inhibitors​ Induction of apoptosis

Human Genome Data Tailor Diagnosis and Treatment Currently, genetic information is refining disease management​ Ex. Breast cancer

Human Genome Data Tailor Diagnosis and Treatment Breast Cancer Diagnosis Physicians determine the type of receptors tumor cells have Estrogen Progesterone prescribe drugs to block specific receptors

Human Genome Data Tailor Diagnosis and Treatment Breast Cancer Diagnosis Physicians also look at genotype to determine specific gene mutations BRCA1 Her-2/neu Helps determine treatments that will be most effective

Human Genome Data Tailor Diagnosis and Treatment Cancer treatments intended to “cure” the disease Usually only slow the spread of cancer Cancer then becomes a chronic, manageable condition