Chapter 16 Flashcards

The genetics of cancer

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1
Q

Intro - cancer

A
  • 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
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2
Q

Cancer is a genetic disease

A
  • 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
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3
Q

Somatic mutations in cancer

A

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
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4
Q

Benign vs Malignant

A

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

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5
Q

Clonal origin of cancer cells

A

clonal origin

  • all cancer cells in primary and secondary tumors are clonal
  • clonal: originated from common ancestral cell that accumulated numerous specific mutations
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6
Q

X-chromosome inactivation

A
  • 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
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7
Q

Reciprocal Chromosome Translocations

A
  • 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
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8
Q

Cancer: multistep process requiring multiple mutations

A

–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.

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9
Q

Carcinogens

A
  • 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
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10
Q

Tumorigenesis

A
  • development of malignant tumor
  • result of 2 or more genetic alterations: progressively release cells from normal controls on cell proliferation and malignancy
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11
Q

Driver mutations

A
  1. 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
  2. Passenger mutations
    - have no direct contribution to cancer phenotype
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12
Q

Cancer cell characteristics

A
  1. Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications
  2. Cancer cells show higher than normal rates of
    - mutation
    - chromosomal abnormalities
    - genomic instability
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13
Q

Genomic instability and defective DNA repair

A

Genomic instability in cancer cells manifests in gross defects

  1. translocations
  2. aneuploidy
  3. chromosome loss
  4. DNA amplification
  5. chromosome deletions
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14
Q

chronic myelogenous leukemia (CML)

A
  • 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)
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15
Q

Chromatin modifications and cancer epigenetics

A

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
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16
Q

Epigenetics of cancer

A

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

17
Q

The cell cycle

A

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

18
Q

Cell Cycle Checkpoints

A

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
19
Q

G1/S, G2/M and M checkpoints

A

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

20
Q

Control of apoptosis

A

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
21
Q

Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells
- proto-oncogenes

A

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

22
Q

Oncogene

A

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
23
Q

Tumor suppressor genes

A

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

24
Q

p53 tumor suppressor gene

A
  • 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
25
Q

p53

A

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
26
Q

Metastasis

A

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
27
Q

Control of metastasis

A
  • 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)
28
Q

Hereditary cancer

A

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)
29
Q

Viruses and Cancer

A

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)
30
Q

More on carcinogens

A
  • 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)
31
Q

Smoking, Drinking, Diet

A

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

32
Q

Natural Substances

A
  • 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
33
Q

UV light and Radiation

A

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)