Cancer Genetics Flashcards
1
Q
cancer
A
-environment plus genes
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
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
4
Q
mets
A
- when cells become invasive or migrate to another site
- retain original cell morphology
- still classified by primary site
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
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
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
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
9
Q
types of genes associated with cancer
A
- proto-oncogenes/ oncogenes
- tumor suppressors
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
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
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
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
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
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
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
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
18
Q
normal functions of tumor suppressors
A
- cell to cell interactions
- regulation of growth inhibitory substances
- cell proliferation
- cell differentiation
- chromosome repair
19
Q
common tumor suppressors
A
- Rb1
- p53 on 17p
- MTS1- common
- WT-1
- APC
- MCC
- DCC
- NF1
- Merlin
- VHL
- MTS1
- BRCA1/ 2
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
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
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
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
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
25
tumor suppressor 3
- 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
familial cancers
- breast and ovarian
- familial polyposis
- retinoblastoma
- von recklinghausen neurofibromatosis
- wilm's tumor
- VHL/ renal cell cancer
27
Li Fraumeni
- 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
breast cancer
- 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
BRCA1 and 2
- 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
complexity of breast cancer
- 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
caretaker mutations
- 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
breakage syndromes
- 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
breakage syndromes 2
- recessive inheritance
- chromosome instability
- defective DNA repair mechanisms
- susceptibility to cancer
34
chromosome instability
- 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
defects in DNA repair genes
- 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
hereditary non-polyposis colon cancer
- 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
mismatch repair
- 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
microsatellites
- 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
HNPCC 2
- 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
summary
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
chromosome instability
- 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
cancer evolution
- 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
clonality
- 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
karyotype evolution
- 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
clinical testing
- 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
constitutional findings
- original DNA and chromosome complement that is the foundation for the genetic constitution in all cells of the body
- originated in zygote
47
acquired anomalies
- a change which has occurred in the constitutional DNA or karyotype
- usually present in a single cell line (clone)
48
chromosome rearrangements
- some indicative of one disease, other present in more than one disease
- could narrow it down
49
Down syndrome
- increased risk for leukemia
| - trisomy 21 is an acquired change in a leukemic cell line in a non-DS patient
50
loss of heterozygosity
- 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
prognosis
- 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
monitoring disease
- 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
APL and FISH
- broadened amt of info we can find
- FISH is quick- more cells can be scored
- only abnormalities being specifically tested
54
FISH
- 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
gene amplification
- 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
BCR-ABL
-95% detected by karyotype or FISH, PCR can be used and detects remaining 5%
57
sequencing
- new tech to id known disease related mutations
- developed signature panels-unique subsets
- connected with tumors
- DNA fingerprint
58
expression arrays
- determine relatedness between difference diseases
- two diseases that are different clinically actually have a common basis?
- expression in normal cells vs cancer cells
59
genetics and cancer
- mutations can be inherited or acquired
- somatic mutation is usually required for disease expression
- multi step process at somatic cell level
60
inherited cancers
- 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
conclusions
- 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
