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
