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Molecular and Cellular Princples of Medicine > Unit 7 - Cancer Genetics > Flashcards

Unit 7 - Cancer Genetics Flashcards

1
Q

what is a “tumor”?

A

overgrowth of cell material

  • solid VS dispersed
  • clonality (proliferate to form group of similarly abnormal cells)
  • benign VS malignant
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2
Q

what is a “malignancy”?

A

uncontrolled cell growth characterized by significant change in normal organizational pattern of tissues or cells

  • tend to be deleterious
  • karyotypic changes
  • metastasis
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3
Q

what is metastasis?

A

cells become invasive and migrate to another site, while maintaining original cell morphology

  • so a tumor in the liver that came from breast cancer cells is still called breast cancer
  • IOW: a primary cancer in a escondary location is known by the primary classification
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4
Q

what is “cancer”

A

malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis

  • overgrowth of cell material (tumor)
  • clonal
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5
Q

what are these types of cancer?

  • sarcoma
  • carcinoma
  • hematopoietic?
A

sarcoma: mesenchymal tissue (bone, cartilage, muscle, fat)
carcinoma: epitheloid tissues
hematopoietic: leukemias (WBC from bone marrow) and lymphomas (WBC from spleen and lymph nodes)

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6
Q

hallmarks of cancer?

A
  • mutation or loss of genes involved in cell control, including growth/division, proliferation, metabolism
  • environmental elements may influence mutation
  • mutations may be inherited or acquired
  • chromosome instability (CIN)
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7
Q

what are the 2 types of genes associated with cancer?

A
  • proto-oncogenes/oncogenes

- tumor suppressors

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8
Q

what is an oncogene?

A

a dominantly acting gene involved in unregulated cell growth and prolfieration that is capable of transforming (changing) host cells
-most are carried by viruses and associated with disease in animals, but only 5 known in humans

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9
Q

what are the 5 known oncogenes in humans?

A
  1. HPV - cervical cancer (E6/7)
  2. EBV - nasopharyngeal cancer, Hodgkin and Burkitt lymphoma
  3. HHV-8 (herpes virus) - Kaposi sarcoma
  4. HTLV-1 - T cell leukemia
  5. HTLV-2 - various leukemias
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10
Q

what are H-ras, sis, and abl?

A

oncogene viruses associated with animal disease

  • Harvey rat sarcoma virus
  • Simian sarcoma virus
  • Abelson murine leukemia virus
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11
Q

what are proto-oncogenes?

A

structurally important “housekeeping” genes necessary in human genome for cell proliferation and development

  • in native state, not associated with disease
  • growth factors, cell surface receptors, intracellular signal transduction, DNA binding PRO (transcription), regulation of cell cycle
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12
Q

what is “activation of a proto-oncogene”? is this a dominant or recessive process?

A

change in the proto-oncogene that converts it oncogene-like for tumorigenesis

  • caused by gain in function mutations (translocation, amplification, point mutations), which changes its gene regulation, transcription, or PRO product
  • this is dominant b/c only 1 mutation is required
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13
Q

what is CML caused by?

A

chronic myelogenous leukemia (relatively common form, mainly in older adults)

  • first leukemia associated with cytogenetic marker t(9,22) proto-oncogene
  • caused by juxtaposition of 2 genes that generates chimeric PRO product with a new function associated with disease
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14
Q

how was treatment for CML discovered?

A

delination of genetic abnormality led to better understanding of proto-oncogenes
-allowed development of new drug targeted to genetic lesion: Gleevec/imatinib BCR/ABL specific tyrosine kinase inhibitor

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15
Q

what is acute promyelocytic leukemia?

A

proto-oncogene related disease characterized by t(15,17) breaking PML gene on 15 and RARA (retinoic acid receptor alpha) gene on 17

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16
Q

how is APL diagnosed via FISH?

A

dual fusion probe shows that the translocation splits the probe recognition site so half of each probe is moved to reciprocal Xm

  • normal will have no rearrangement, but if positive, there are 2 fusion signals
  • NEED POSITIVE FISH in order to have diagnosis of APL
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17
Q

how does FISH aid in APL disease monitoring?

A
  • if normal signal patterns return after treatment, the patient has responded to therapy (gone into remission)
  • if fusion pattern returns, patient has relapsed
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18
Q

what is a tumor suppressor? how is activity lost? is it dominant or recessive?

A

genetic element whose loss or inactivation allows cell to display alternate phenotype leading to neoplastic growth

  • oncogenetic potential when gene activity is lost (deletions, Xm gain/loss, gene mutation)
  • recessive b/c needs both alleles mutated
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19
Q

what are the 2 major subgroups of tumor suppressors?

A
  1. gate keepers: suppress tumors by regulating cell cycle or growth inhibition
  2. caretakers: repair DNA damage and maintain genomic integrity
    - effect is indirect - accumulation of errors in cells (just one loss of function may not be linked directly to disease)
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20
Q

what is the normal function of tumor suppressor genes, whose loss can lead to disease?

A
  • cell-cell interactions
  • regulation of growth inhibitory substances
  • cell proliferation
  • cell differentiation
  • Xm repair
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21
Q

what kinds of genes are RB1, p53, and MTS1?

A

they are all tumor suppressor genes

  • RB1 on 13
  • p53 on 17; one of most ubiquitous tumor suppressors
  • -mutations identified in nearly all types of cancer
  • MTS1 on 9; multiple tumor suppressor 1
22
Q

are solid tumors or leukemia/lymphomas more common in mutations of proto-oncogenes or tumor suppressors?

A

solid tumor - tumor suppressor mutation

leukemia/lymphoma - proto-oncogene mutation

23
Q

what is an Rb1 mutation?

A 
classic gatekeeper (tumor suppressor) mutation, commonly a mutation in Xm 13q14.2
-controls progression from G1 to S, so loss of function eliminates checkpoint causing uncontrolled growth

primary cancer: retinoblastoma
secondary cancer: osteosarcoma

24
Q

what is a retinoblastoma?

A

tumor of retinoblasts (immature retinal cells) of eye

  • 1/20,000, from prenatal to 5 years old
  • once retinoblasts mature to retinal cells at 5 years, the target tissue of disease is gone, and disease cannot occur
  • can be unilateral (often sporadic) or bilateral (often inherited)
  • if untreated, tumor can grow forward, out of the skull, and back into the brain (last is lethal)
  • -some can treat with laser surgery (leaves blind spot on retina), severe cases need enucleation
  • can have secondary osteosarcoma in teens
25
Q

inherited VS sporadic mechanism of tumor suppressor gene mutation

A

remember that tumor suppressor gene mutations are recessive; need 2 mutated alleles to see tumor

inherited: will have one mutated allele from affected parent
- patient will have 1 somatic (sporadic) mutation in order to have cancer

sporadic: patient is born normal, but along the way gets 2 different mutations

26
Q

what is Knudson’s “two-hit” hypothesis for retinoblastoma?

A

two mutations in the same cell are needed to start cancer

  • sporadic usually unilateral
  • inherited usually bilateral
  • appearance of dominance, even though gene itself is recessive
27
Q

somatic VS familial cancers in relation to age of onset

A

somatic - usually older age of onset (needs both sporadic mutations)
familial - usually younger onset (only needs 1 more mutation)

28
Q

what is Li Fraumeni?

A

familial cancer syndrome with inheritance of p53 mutation

  • p53 has no one target tissue and not specific to one disease, thus multiple neoplasia
  • increased risk of cancer (50% at age 30, 90% at age 70)
29
Q

what is the lifetime risk of breast cancer? mutations? is it familial or sporadic? what genes are associated with it?

A

1/8 to 1/10, can be familial or sporadic, with errors in homologous recombination or DNA repair defects
-2 known genes: BRCA1 (Xm 17, near NF1 and p53), BRCA2 (Xm 13, near Rb1)

30
Q

how are BRCA1 and 2 related to breast cancer?

A

in 80-90% of familial breast cancer (should review pedigrees to assess risk)

  • in 5-9% of all breast cancer
  • multiple mutations
  • increased risk of male breast cancer
  • increased risk in Ashkenazi Jewish population
31
Q

what are caretaker mutations?

A

type of tumor suppressor gene mutation

  • inability to repair DNA defects/mutations
  • -accumulation of abnormal DNA/genes
  • -increase in genome instability (breakage syndromes)
  • -may lead to mutations of proto-oncogenes or tumor suppressor genes
  • inherited or acquired
32
Q

what are examples of familial cancers?

A
  1. breast/ovarian cancer
  2. familial polyposis coli
  3. retinoblastoma
  4. von Recklinghausen neurofibromatosis
  5. Wilm’s tumor
  6. von Hippel Lindau/renal cell cancer
33
Q

what are examples of breakage syndromes?

A
  1. Fanconi anemia
  2. Bloom syndrome - DNA ligase 1 or DNA helicase mutation
  3. Ataxia telangiectasia
  4. Xeroderma pigmentosum - excision repair
  5. Cockayne syndrome - excision repair cross complementation
34
Q

what are chromosomal breakage syndromes?

A

diverse group of diseases with different clinical phenotypes, and caused by genes on different Xms

  • recessive inheritance
  • Xm instability
  • defective DNA repair mechanisms
  • susceptibility to cancer
35
Q

what is sister chromatid exchange?

A

exchange of gene regions between sister chromatids

  • normal event, and in normal cells, it causes a swap of identical pieces of DNA
  • errors can occur with unequal changes, causing duplication of sequences on one chromatid, and deletion in others
  • -usually repaired in normal cells, but not if mutation in DNA repair gene
36
Q

what are triradials?

A

instead of normal linear Xm, a replication error has resulted in a Y-shaped or forked structure (end of Xm was copied again)

37
Q

what is hereditary nonpolyposis colon cancer? risks? most important types and genes associated with it?

A

2-4% of hereditary colon cancer

  • 90% lifetime risk for males who inherit one mutation
  • 70% lifetime risk for females who inherit one mutation
  • -40% endometrial cancer, 10-20% urinary tract cancer, 10-20% ovarian cancer

HNPCC1 - gene MSH2
HNPCC2 - gene MLH1 (with HNPCC1, 70-80% of cases)
HNPCC5 - gene MSH6 (only 7-10% cases)

38
Q

what are microsatellites? how are they related to HNPCC tumor tissue?

A

repeats of 2, 3, or 4 nucleotides that are highly polymorphic in population

  • these are present throughout genome, and sequencing is used in DNA fingerprinting
  • subject to replication error due to slippage, and mutations in mismatch repair can alter total number of repeats
  • presence of extra bands in putative HNPCC tumor tissue is consistent with disease diagnosis (but not a direct test)
39
Q

is HNPCC a gene mutation, or a malfunction in normal cellular process?

A

HNPCC is a malfunction in a normal cellular process, that in and of itself is not deleterious
-accumulation of errors eventually results in system dysfunction

40
Q

what is chromosome instability?

A

de novo

  • breakage or recombination
  • Xm rearrangement
  • -duplications or deletions
  • -translocations or inversions
  • -tandem duplication of genes
  • -generation of supernumary Xm
  • gain or loss of whole Xm
41
Q

what is “cancer evolution”?

A

since cancer is complex and needs more than one step, progression requires a combo of environmental and gene effects

  • many different mutations arise, but key principle is that they must occur within a single cell
  • -need gatekeeper (APC), proto-oncogene (Ras), and other tumor suppressor genes (DCC, p53) to see effect
42
Q

what is clonality?

A

normal cell may have single mutation that proliferates and generates abnormal clone (acquired change in a limited number of cells)

  • further Xmal changes can modify karyotype and make more clones
  • karyotype analysis monitors presence and evolution of clones
43
Q

what is karyotype evolution?

A

change over time in karyotype due to acquisition of different mutations

  • increasing complexity and numbers of Xm abnormalities are usually associated with poorer prognosis
  • possible to use Xm abnormalities to follow patient from diagnosis to remission and relapse
44
Q

what does clinical testing of cancer require?

A
  • detection of molecular and Xmal anomalies associated with disease
  • -diagnosis, prognosis
  • -monitor remission and relapse
  • -must have baseline
  • molecular diagnostics
  • cytogenetics (karyotype and FISH)
45
Q

what is a constitutional finding?

A

either karyotype or genotype

  • original DNA and Xm complement that is foundation for genetic constitution in all cells of body
  • originated in zygote
46
Q

what are acquired anomalies?

A

change in constitutional DNA or karyotype

-usually present in a single cell line (clone)

47
Q

what do unique VS non unique Xm rearrangements mean?

A

unique = specific diagnosis

not unique = general diagnosis

48
Q

what is the link between Down syndrome and leukemia?

A

have 10-15x increased leukemia rate b/c third Xm 21 had RUNX1 (AML1)

49
Q

what is loss of heterozygosity?

A

apparent homozygosity or hemizygosity in a tissue which usually demonstrates heterozygosity

  • in one locus, one Xm arm, or entire Xm
  • doesn’t mean only one allele present (can have 3 of one Xm)
50
Q

remission VS relapse

A

remission: treatment suppresses disease (no clinical symptoms)
relapse: Xmal or molecular abnormalities reappear

51
Q

how is FISH better than karyotype analysis?

A

takes 18-24 hours, and much quicker with higher statistical significance than karyotype study

52
Q

how is gene amplification related to breast cancer?

A

specifically HER-1/neu type breast cancer

-with gene amplification, responds to drug herceptin better than without gene amplification

Molecular and Cellular Princples of Medicine (42 decks)

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