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MCP Unit 7 > Cancer Genetics > Flashcards

Cancer Genetics Flashcards

1
Q

cancer

A

-environment plus genes

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2
Q

tumor

A
  • overgrowth of cell material
  • solid vs dispersed
  • clonality
  • benign-milder, usually harmless, non progressive disease, doesn’t metastasize
  • malignant
  • single cell with a mutation that proliferates to form a group
  • can get additional mutations
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3
Q

malignancy

A
  • uncontrolled cell growth characterized by a change in the normal organizational pattern of tissues or cells
  • karyotypic changes, mets
  • malignant tumors tend to be deleterious and may metastasize
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4
Q

mets

A
  • when cells become invasive or migrate to another site
  • retain original cell morphology
  • still classified by primary site
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5
Q

cancer 2

A
  • malignant tumor of potentially unlimited growth that expands locally by invasion and systemically my mets
  • overgrowth of cell material
  • clonal
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6
Q

types of cancer

A
  • sarcoma- mesenchymal tissue (bone, cart, muscle, fat)
  • carcinoma-epitheloid tissues
  • hematopoietic/lymphoid- leukemias (WBC from bone marrow) and lymphomas (WBC from spleen and lymph nodes
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7
Q

environment

A
  • mutagens:
  • UV, asbestos, cigarette smoke, plastics, dyes
  • effect changes in normal cell regulation and/or development
  • additional element in cancer induction
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8
Q

hallmarks of cancer

A
  • mutation of 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
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9
Q

types of genes associated with cancer

A
  • proto-oncogenes/ oncogenes

- tumor suppressors

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10
Q

oncogene

A
  • dominantly acting gene involved in unregulated cell growth and proliferation
  • carried by viruses
  • associated with disease in animals
  • H-ras-harvey rat sarcoma virus
  • sis-simian sarcoma virus
  • abl-abelson murine leukemia virus
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11
Q

viral oncogenes in humans

A
  • HPV
  • EBV-nasopharyngeal cancer, hodgkin and burkitt lymphoma
  • HHV-8- herpes- kaposi sarcoma
  • HTLV1- T cell leukemia
  • HTLV-2- various leukemias

-mutation of proton oncogene in humans/ other mammals

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12
Q

proto-oncogene

A
  • structurally important housekeeping genes involved in cell proliferation and development
  • GF
  • cell surface receptors
  • intracellular signal transduction
  • DNA binding proteins
  • regulation of cell cycle
  • mutation can result in activation of proto-oncogene
  • this may cause a change in gene regulation, transcription, or a protein product generating alterations to cell growth, proliferation, or differentiation
  • can lead to tumorigenesis
  • gain of function mutation
  • dominant- only 1 mutation required
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13
Q

CML

A
  • relatively common form of leukemia
  • first one associated with genetic marker- Ph chromosome
  • delineation of the genetic abnormality led to a better understanding of proto-oncogenes
  • allowed development of a new class of drug- targeting to genetic lesion
  • gleevec-BCR-ABL specific tyrosine kinase inhibitor
  • molecular analysis led to new ideas about treatment of disease
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14
Q

APL

A
  • acute promyelocytic leukemia
  • 15,17 translocation, breaks PML gene on 15 and RARA gene on 17
  • chimeric protein product
  • dual fusion probe
  • half of each probe is moved to reciprocal chromosome
  • 1 red, 1 green and two yellow signals
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15
Q

15,17 translocation

A
  • clinically diagnostic of APL and is required for a positive diagnosis of the disease
  • results in a fusion signal found by FISH
  • aids in diagnosis and monitoring
  • if normal signal pattern returns after treatment- remission
  • fusion returns- relapse
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16
Q

tumor suppressor

A
  • genetic element whose loss or inactivation allows the cell to display an alternate phenotype leading to neoplastic growth
  • oncogenic potential when gene is lose
  • recessive
  • normally prevent overgrowth
  • need 2 hits
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17
Q

tumor suppressor 2

A
  • gate keepers- suppress tumors by regulating cell cycle or growth inhibition
  • caretakers- repair DNA damage and maintain genomic integrity
  • effect is indirect- accumulation of errors in cell
  • increase in genomic instability
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18
Q

normal functions of tumor suppressors

A
  • cell to cell interactions
  • regulation of growth inhibitory substances
  • cell proliferation
  • cell differentiation
  • chromosome repair
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19
Q

common tumor suppressors

A
  • Rb1
  • p53 on 17p
  • MTS1- common
  • WT-1
  • APC
  • MCC
  • DCC
  • NF1
  • Merlin
  • VHL
  • MTS1
  • BRCA1/ 2
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20
Q

solid tumors

A
  • mutations of tumor suppressors are often expressed as solid tumors
  • difficult to culture, but karyotype analysis can be useful, but chromosome changes aren’t always found
  • number of diseases are known to have specific chromosomal changes, so this information can be used in classification
  • most tumor suppressors are tissue specific- mutations will only cause disease in 1 or 2 cell types
  • benign tumors can have chromosome changes and malignant can have none
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21
Q

Rb1

A
  • classic gatekeeper mutation
  • functions in regulation of the cell cycle
  • controls progression of G1 to S
  • loss of function eliminates an important mitotic checkpoint, resulting in uncontrolled growth
  • on chromosome 13q 14.2
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22
Q

retinoblastoma

A
  • 1/20,000
  • prenatal to 5 years old
  • tumor of retinoblasts
  • once they mature to retinal cells the target tissue is gone and so you can’t get disease after this point
  • uni or bilateral
  • if untreated can grow forward or backwards
  • some may be treated by laser surgery
  • severe cases require enucleation
  • sporadic is usually unilateral
  • inherited is often bilateral
  • secondary cancer is osteosarcoma
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23
Q

mechanism of retinoblastoma

A
  • if one is inherited, then all the cells will have 1 mutation
  • disease is tissue specific
  • if second mutation of RB1 locus occurs in any retinoblast cell, the probability of a tumor is high
  • more than one mutation can occur , so that several tumors in one or both eyes can occur
  • mutation rate is 10^-6 and 10^7 cells- probability is high- penetrance of 90%
  • if no inherited mutation, both have to occur on the somatic level
  • 2 mutations in one cell
  • probability is low
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24
Q

two hit hypothesis

A
  • two mutations in the same cell
  • sporadic usually unilateral
  • inherited usually bilateral
  • appearance of dominance
  • gene itself isn’t dominant- tumor suppressors are recessive
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25
Q

tumor suppressor 3

A
  • primary mutation has a specific tissue target
  • can be secondary to another cancer gene
  • somatic usually occur at older ages (takes longer to get 2 mutations)
  • familial usually occur younger (2nd mutation doesn’t take as long)
26
Q

familial cancers

A
  • breast and ovarian
  • familial polyposis
  • retinoblastoma
  • von recklinghausen neurofibromatosis
  • wilm’s tumor
  • VHL/ renal cell cancer
27
Q

Li Fraumeni

A
  • familial cancer syndrome
  • multiple neoplasia
  • increased risk of cancer
  • 50% at age 30
  • 90% at age 70
  • inherited mutation of p53
  • breast, lung, colon, prostate, brain
  • soft tissue sarcoma, breast cancer, adenocortical cancer, leukemia, brain tumors, osteosarcoma, melanoma, gonadal germ cell tumor, lung, prostate
28
Q

breast cancer

A
  • lifetime risk of 1/8 to 1/1
  • familial or sporadic
  • mutations: errors in homologous recombinations, DNA repair defects
  • 2 known genes
  • familial onset is 20s-40s, uni or bilateral
  • 5-10% of all breast cancers
  • one inherited mutation, penetrance is 80-90%
  • sporadic accounts for 90-95% of all breast cancer cases
  • later onset, usually unilateral
  • complex disease with many patient issues
29
Q

BRCA1 and 2

A
  • two primary genes associated with breast cancer
  • 1 is on 17 near NF1 and p53
  • 2 is on chromosome 13 near Rb1
  • 80-90% of familial breast cancer- review of pedigrees to assess risk followed by testing when appropriate
  • 5-9% of all breast cancer
  • multiple mutations
  • increased risk of male breast cancer
  • increased risk in Ashkenazi Jew pop
  • counseling is critical
30
Q

complexity of breast cancer

A
  • many people in family
  • cousin diagnosed but sister negative
  • survivor guilt- can be as damaging as if they actually had cancer
  • still at risk for sporadic if negative for the familial
  • males can also get breast cancer
  • mortality is high in males because they don’t look for help quickly enough
  • males who are at risk for familial can pass it on to their daughters
31
Q

caretaker mutations

A
  • inability to repair DNA defects/ mutations
  • accumulation of abnormal DNA/genes
  • increase in genome instability
  • may lead to mutation of proto-oncogenes or tumor suppressor genes
  • inherited or acquired
  • fanconi anemia
  • ataxia telangiectasia
  • breast cancer
  • HNPCC-colon
  • bladder cancer
32
Q

breakage syndromes

A
  • fanconi anemia- 9q22.3, 11q23, 20q13
  • bloom syndrome- 15q26.1-DNA ligase 1 or DNA helicase
  • ataxia telangiectasia 11q22-q23
  • xeroderma pigmentosum- 3p25, 13q33, ch 9- excision repair
  • cockayne syndrome 5q12, 10 q11, excision repair cross complementation
33
Q

breakage syndromes 2

A
  • recessive inheritance
  • chromosome instability
  • defective DNA repair mechanisms
  • susceptibility to cancer
34
Q

chromosome instability

A
  • the breakage syndromes were linked because of common finding of chromosome instability or fragility
  • sister chromatid exchange-normally results in swap of identical DNA. errors can occur and unequal exchanges can take place- duplications or deletions, may not be repaired with DNA repair gene mutations
  • triradials-Y shaped or forked structure due to replication error
  • excessive breakage of chromosomes can lead to deletion and genomic defects
35
Q

defects in DNA repair genes

A
  • inability to repair DNA defects/ mutations
  • accumulation of abnormal DNA/genes
  • increase in genome instability
  • may lead to mutation of proto-oncogenes or tumor suppressor genes
  • inherited or acquired
  • fanconi anemia
  • ataxia telangiectasia
  • breast cancer
  • HNPCC-colon
  • bladder cancer
36
Q

hereditary non-polyposis colon cancer

A
  • 204% of hereditary colon cancer
  • 90% lifetime risk for males who inherit one mutation
  • 70% risk for females who inherit on mutation
  • 40% of endometrial cancer
  • 10-20% risk of urinary tract cancer
  • 10-20% risk of ovarian cancer
  • multiple genes involved
  • MSH6 accounts for 7-10% of cases
  • TGFBR2 is not mismatch repair- its growth factor receptor
  • HNPCC7 has been reported in only a single case
37
Q

mismatch repair

A
  • if error occurs, it is detected by error checking enzyme
  • defect is excised along with adjacent bases, missing bases are filled in, fragment ligated back to DNA
  • if process doesn’t work, error isn’t detected- during next cycle both will be replicated- 2 cell lines
38
Q

microsatellites

A
  • repeats of 2, 3, or 4 nucleotides
  • highly polymorphic in population
  • repair defects can be detected by analysis of microsatellites
  • subject to replication error due to slippage
  • mutations in mismatch repair can alter total number of repeats
  • presence of extra bands in putative HNPCC tumor tissue is consistent with disease diagnosis
  • because expected patterns have been catalogued
39
Q

HNPCC 2

A
  • microsatellite analysis suggests the presence of defect in mismatch repair
  • finding is consistent with a mutation in one of the 5 genes associated with HNPCC
  • DNA instability leads to additional mutations throughout the genome- can affect tumor suppressors
  • not a direct test- trying to asses effect mutation has had on loci throughout the genome
  • not gene mutation–>aberrant protein–> disease
  • it’s a malfunction in a normal cellular process that in and of itself is not deleterious
  • the accumulation of errors eventually results in system dysfunction
40
Q

summary

A

proto-oncogene mutations:

  • dominant
  • acquired
  • chromosome translocation, amplification, point mutation
  • primary target- leukemias/lymphomas
  • gain or change of function

tumor suppressor mutations:

  • recessive
  • 1 mutation may be inherited
  • deletions, chromosome gain/loss, gene mutation
  • primary target- solid tumors
  • loss of function
  • gate keeper or caretaker functions

error accumulation-DNA repair defects- increased breakage and rearrangement in some diseases

41
Q

chromosome instability

A
  • de novo- breakage or recombination
  • chromosome rearrangement:
  • duplications or deletions
  • translocations or inversions
  • tandem duplications of genes
  • generation of supernumerary chromosomes
  • gain or loss of whole chromosomes
42
Q

cancer evolution

A
  • requires more than one step
  • combo of environment and genes
  • many different mutations all within one cell
  • some mutations are specific to particular steps in disease process
  • all must occur and all in the same cell, but not in sequential order. Disease happens after they are all present
  • person with inherited mutation has a jump start on the process
  • APC is a gate keeper
43
Q

clonality

A
  • normal cell may have a single mutation, which proliferates and generates an abnormal clone
  • this is an acquired change in a limited number of cells
  • further chromosomal changes may modify the karyotype and produce additional clones
  • can use karyotype analysis to monitor
44
Q

karyotype evolution

A
  • change over time in karyotype due to acquisition of different mutations
  • generally, increasing complexity and numbers of chromosome abnormalities are associated with poorer prognosis
  • possible to use chromosome abnormalities to follow patient from diagnosis to remission to relapse
45
Q

clinical testing

A
  • detection of molecular and chromosomal abnormalities associated with disease
  • diagnosis and prognosis
  • monitor remission and relapse
  • must have baseline
  • molecular diagnostics
  • cytogenetics- karyotype and FISH
  • need targeted tests, need mutation or cellular change
46
Q

constitutional findings

A
  • original DNA and chromosome complement that is the foundation for the genetic constitution in all cells of the body
  • originated in zygote
47
Q

acquired anomalies

A
  • a change which has occurred in the constitutional DNA or karyotype
  • usually present in a single cell line (clone)
48
Q

chromosome rearrangements

A
  • some indicative of one disease, other present in more than one disease
  • could narrow it down
49
Q

Down syndrome

A
  • increased risk for leukemia

- trisomy 21 is an acquired change in a leukemic cell line in a non-DS patient

50
Q

loss of heterozygosity

A
  • apparent homozygosity or hemizygosity in a tissue which demonstrates heterozygosity constitutionally
  • 1 locus
  • 1 chromosome arm
  • entire chromosome
  • doesn’t mean there is only a single allele present
  • can have multiple copies of chromosome with only a single band on DNA analysis
  • loss of one of originals and duplication of remaining
  • new mutations constantly found- need correlation
51
Q

prognosis

A
  • in some instances, there is a direct correlation between a particular chromosomal finding and the course of the disease
  • knowing that info may aid in determining the type of treatment used
  • more resistant disease treated more aggresively
52
Q

monitoring disease

A
  • at diagnosis, both normal and cancer cells are present
  • treatment will hopefully cure patient
  • often, treatment suppresses disease-remission
  • patient can then relapse, chromosomal abnormalities will re appear
53
Q

APL and FISH

A
  • broadened amt of info we can find
  • FISH is quick- more cells can be scored
  • only abnormalities being specifically tested
54
Q

FISH

A
  • successful in monitoring bone marrow transplant patients
  • easy on mixed sex transplants
  • scored for 2 Xs aor a X,Y to determine proportions
  • quicker and higher statistical significance than karyotype study
  • donor cell line should populate marrow
55
Q

gene amplification

A
  • another type of anomaly seen in cancers
  • one type of breast cancer responds to herceptin, but it isn’t effective in cells without amp
  • FISH detects amplification
  • HER2-neu
  • tumor cells have multiple copies
56
Q

BCR-ABL

A

-95% detected by karyotype or FISH, PCR can be used and detects remaining 5%

57
Q

sequencing

A
  • new tech to id known disease related mutations
  • developed signature panels-unique subsets
  • connected with tumors
  • DNA fingerprint
58
Q

expression arrays

A
  • determine relatedness between difference diseases
  • two diseases that are different clinically actually have a common basis?
  • expression in normal cells vs cancer cells
59
Q

genetics and cancer

A
  • mutations can be inherited or acquired
  • somatic mutation is usually required for disease expression
  • multi step process at somatic cell level
60
Q

inherited cancers

A
  • carrier parent has a 50% chance of passing on mutation
  • second mutation occurs at somatic level
  • risk correlated to number and degree of affected relatives
  • inherited mutation means an increased risk in acquiring the disease
61
Q

conclusions

A
  • primary genetic causes of cancer can be linked to oncogenes, tumor suppressor genes
  • many diseases now have clinical testing available
  • new technologies are providing new diagnostic methods and new treatments

MCP Unit 7 (14 decks)

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