Chapter 16 Flashcards
The genetics of cancer
Intro - cancer
- the leading cause of death in Western countries
- Genetic disease at somatic level, characterized by gene products derived from mutated or abnormally expressed genes
- some inherited, most are created within somatic cells that divide and form tumors
- more than 1 million cases diagnosed in the US each year, 500,000 deaths
Cancer is a genetic disease
- Genomic alterations assoc with cancer include:
1. single nucleotide substitutions
2. chromosomal rearrangements
3. amplifications and deletions - cancer caused by mutations in somatic cells
- only 5 % of cancers are assoc with germline mutations
Somatic mutations in cancer
Cancer: genetic disease at somatic level
- results from mutated gene products or abnormally expressed genes
- mutations affect multiple cellular functions
- cancer cells share two fundamental properties:
1. abnormal cell growth and division: unregulated cell proliferation
2. metastatic spread
Benign vs Malignant
Benign tumors
- result from unregulated cell growth that forms a multicellular mass
- removed by surgery, causing no serious harm
Malignant tumors
- result from metastasized cells invading other tissue and causing life-threatening problems
Clonal origin of cancer cells
clonal origin
- all cancer cells in primary and secondary tumors are clonal
- clonal: originated from common ancestral cell that accumulated numerous specific mutations
X-chromosome inactivation
- occurs early in development at random
- all cancer cells within a tumor contain the same inactivated X chromosome
- supports concept that all cancer cells in patients arise from common ancestral cell
Reciprocal Chromosome Translocations
- characteristic of many cancers
- include WBC cancers such as leukemias and lymphomas
- ex: Burkitt lymphoma - reciprocal translation b/w chromosome 8 and chromosome 2, 14, 22
Cancer: multistep process requiring multiple mutations
–Age-related incidence of cancer indicates cancer develops from accumulation of several mutagenic events in a single cell.
–Incidence of most cancers rises exponentially with age –Independent and random mutations are necessary for cells to become malignant.
Carcinogens
- cancer causing agents
- delay between exposure to carcinogen and appearance of cancer is an indication of a multistep process
- ex: leukemia from radiation exposure (at Hiroshima) had an incubation period of 5 to 8 years
Tumorigenesis
- development of malignant tumor
- result of 2 or more genetic alterations: progressively release cells from normal controls on cell proliferation and malignancy
Driver mutations
- Driver mutations give growth advantage to tumor cells
- ten of thousands of somatic mutations are present in cancer cells
- the presence of fewer than a dozen mutated genes may be sufficient to create a cancer cell - Passenger mutations
- have no direct contribution to cancer phenotype
Cancer cell characteristics
- Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications
- Cancer cells show higher than normal rates of
- mutation
- chromosomal abnormalities
- genomic instability
Genomic instability and defective DNA repair
Genomic instability in cancer cells manifests in gross defects
- translocations
- aneuploidy
- chromosome loss
- DNA amplification
- chromosome deletions
chronic myelogenous leukemia (CML)
- involves translocation of C-ABL gene on chromosome 9 into BCR gene on chromosome 22
- structure known as Philadelphia chromosome
- (translocated chromosome contains both BCR and ABL genes)
Chromatin modifications and cancer epigenetics
Epigenetics
- study of factors that affect gene expression but do not alter nucleotide sequence of DNA
- may be present in somatic and germ-line cells
- ex of modifications:
1. DNA methylation
2. histone acetylation and phosphorylation
Epigenetics of cancer
DNA methylation is responsible for
- gene silencing associated with parental imprinting
- heterochromatin gene expression
- X- chromosome inactivation
Histone modifications are disrupted in cancer cells
- genes that encode histone-modifying enzymes are often mutated or aberrantly expressed in cancer cells
The cell cycle
cellular events in sequence from 1 division to another
- phases:
- interphase
- G1
- S phase
- G2
- M phase
Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation and Apoptosis
Cell Cycle Checkpoints
G1/S, G2/M and M checkpoints
- three checkpoints where cell monitors external signals and internal equilibrium
- cell decides whether to proceed to next stage of cell cycle
G1/S, G2/M and M checkpoints
G1/S
- checkpoints monitor cell size and determine whether DNA has been damaged
G2/M
- physiological conditions as checked (once G1/S passed) prior to mitosis
M checkpoints
- formation of spindle-fiber system and attachment of spindle fibers to kinetochores associated with centromeres are monitored
Control of apoptosis
apoptosis
- programmed cell death
- occurs when DNA or chromosome damage is too severe to repair
- cells halt progress through cell cycle
- prevent cancer
- eliminates cells not contributing to final adult organism
Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells
- proto-oncogenes
Proto-oncogenes
- genes whose products promote cell growth and division
Encode:
- transcription factors that stimulate expression of other genes
- signal transduction molecules that stimulate cell division
- cell-cycle regulators that move cell through cell cycle
Oncogene
Oncogene: cancer causing gene
- mutated or aberrantly expressed proto-oncogene - Gain of function alteration
- only 1 allele of proto-oncogene needs to be mutated or misexpressed in order to trigger uncontrolled growth
- oncogenes confer dominant cancer phenotype
Tumor suppressor genes
tumor suppressor genes
- regulate cell cycle checkpoints and initiate process of apoptosis
mutated tumor suppressor genes
- unable to respond to cell-cycle to cell cycle checkpoints or undergo apoptosis
- leads to more mutations and development of cancer
p53 tumor suppressor gene
- most frequently mutated gene (50% of all cancers)
- encodes transcription factor that represses or stimulates transcription different genes
- continuously synthesized but rapidly degraded: present at low levels
p53
can arrest cell cycle at several phases
- cells lacking p53 are unable to arrest at cell cycle checkpoints or enter apoptosis
- cellular stress events increase p53 levels
1. DNA damage
2. double stranded breaks in DNA
3. Presence of DNA repair intermediates due to UV light
Metastasis
Cancer cells metastasize and invade other tissues
- to metastasize from the primary tumor, cancer cells must digest components of extracellular matrix (EM) and basal lamina (BL)
- EM and BL normally separate body’s tissues and inhibit migration of cells
Control of metastasis
- once cancer cells have disengaged, they enter blood or lymphatic system
- 0.01% become metastatic cells become tumors
- metastasis is controlled by a large number of gene products (Cell adhesion molecules, cytoskeleton regulators, proteolytic enzymes)
Hereditary cancer
Predisposition to SomeCancers Can Be Inherited
- most cancers result from somatic cell mutations
- however, 50 forms of hereditary cancer (1-2%) are known
- ex: breast cancer (BRCA1), retinoblastoma (RB1)
Viruses and Cancer
Viruses and Environmental Agents Contribute to Human Cancers
- 15% of cancers are associated with viruses
- environmental agents also contribute to cancer development (any substance that changes DNA has a potential to be carcinogenic)
- ex: HPV 16, 18 (cervical cancer), HBV, HCV (hepatocellular carcinoma)
More on carcinogens
- any substance or event that changes DNA and cause mutations to occur in proto-oncogenes or tumor suppressor genes
- include chemicals, radiation, some viruses, and chronic infections
- can be natural or human made (our environment contains abundant carcinogens)
Smoking, Drinking, Diet
Tobacco smoke
- most significant environmental carcinogen
- contains at least 60 mutagenic chemicals, giving smokes a 20 fold increase risk of developing lung cancer
Red meat and animal fat
- associated with colon, prostate, and breast cancer
Alcohol
- may cause inflammation and lead to liver cancer
Natural Substances
- some natural substances and natural process are potentially carcinogenic
- aflatoxic: mold on bread and corn (one of the most carcinogenic chemicals known
- naturally occurring nitrosamines, used as meat preservatives (known to cause cancer)
- naturally occurring pesticides and antibiotics in plants can be carcinogenic
UV light and Radiation
Both UV and ionizing radiation (XR and gamma rays) induce DNA damage
- UV sunlight can cause skin cancer
- DNA lesions are brought on by natural radiation (XR, UV light)
