Unit 7 - Cancer Genetics Flashcards
what is a “tumor”?
overgrowth of cell material
- solid VS dispersed
- clonality (proliferate to form group of similarly abnormal cells)
- benign VS malignant
what is a “malignancy”?
uncontrolled cell growth characterized by significant change in normal organizational pattern of tissues or cells
- tend to be deleterious
- karyotypic changes
- metastasis
what is metastasis?
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
what is “cancer”
malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis
- overgrowth of cell material (tumor)
- clonal
what are these types of cancer?
- sarcoma
- carcinoma
- hematopoietic?
sarcoma: mesenchymal tissue (bone, cartilage, muscle, fat)
carcinoma: epitheloid tissues
hematopoietic: leukemias (WBC from bone marrow) and lymphomas (WBC from spleen and lymph nodes)
hallmarks of cancer?
- 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)
what are the 2 types of genes associated with cancer?
- proto-oncogenes/oncogenes
- tumor suppressors
what is an oncogene?
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
what are the 5 known oncogenes in humans?
- HPV - cervical cancer (E6/7)
- EBV - nasopharyngeal cancer, Hodgkin and Burkitt lymphoma
- HHV-8 (herpes virus) - Kaposi sarcoma
- HTLV-1 - T cell leukemia
- HTLV-2 - various leukemias
what are H-ras, sis, and abl?
oncogene viruses associated with animal disease
- Harvey rat sarcoma virus
- Simian sarcoma virus
- Abelson murine leukemia virus
what are proto-oncogenes?
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
what is “activation of a proto-oncogene”? is this a dominant or recessive process?
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
what is CML caused by?
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
how was treatment for CML discovered?
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
what is acute promyelocytic leukemia?
proto-oncogene related disease characterized by t(15,17) breaking PML gene on 15 and RARA (retinoic acid receptor alpha) gene on 17
how is APL diagnosed via FISH?
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
how does FISH aid in APL disease monitoring?
- if normal signal patterns return after treatment, the patient has responded to therapy (gone into remission)
- if fusion pattern returns, patient has relapsed
what is a tumor suppressor? how is activity lost? is it dominant or recessive?
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
what are the 2 major subgroups of tumor suppressors?
- 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 cells (just one loss of function may not be linked directly to disease)
what is the normal function of tumor suppressor genes, whose loss can lead to disease?
- cell-cell interactions
- regulation of growth inhibitory substances
- cell proliferation
- cell differentiation
- Xm repair
what kinds of genes are RB1, p53, and MTS1?
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
are solid tumors or leukemia/lymphomas more common in mutations of proto-oncogenes or tumor suppressors?
solid tumor - tumor suppressor mutation
leukemia/lymphoma - proto-oncogene mutation
what is an Rb1 mutation?
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
what is a retinoblastoma?
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
inherited VS sporadic mechanism of tumor suppressor gene mutation
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
what is Knudson’s “two-hit” hypothesis for retinoblastoma?
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
somatic VS familial cancers in relation to age of onset
somatic - usually older age of onset (needs both sporadic mutations)
familial - usually younger onset (only needs 1 more mutation)
what is Li Fraumeni?
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)
what is the lifetime risk of breast cancer? mutations? is it familial or sporadic? what genes are associated with it?
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)
how are BRCA1 and 2 related to breast cancer?
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
what are caretaker mutations?
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
what are examples of familial cancers?
- breast/ovarian cancer
- familial polyposis coli
- retinoblastoma
- von Recklinghausen neurofibromatosis
- Wilm’s tumor
- von Hippel Lindau/renal cell cancer
what are examples of breakage syndromes?
- Fanconi anemia
- Bloom syndrome - DNA ligase 1 or DNA helicase mutation
- Ataxia telangiectasia
- Xeroderma pigmentosum - excision repair
- Cockayne syndrome - excision repair cross complementation
what are chromosomal breakage syndromes?
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
what is sister chromatid exchange?
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
what are triradials?
instead of normal linear Xm, a replication error has resulted in a Y-shaped or forked structure (end of Xm was copied again)
what is hereditary nonpolyposis colon cancer? risks? most important types and genes associated with it?
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)
what are microsatellites? how are they related to HNPCC tumor tissue?
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)
is HNPCC a gene mutation, or a malfunction in normal cellular process?
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
what is chromosome instability?
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
what is “cancer evolution”?
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
what is clonality?
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
what is karyotype evolution?
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
what does clinical testing of cancer require?
- detection of molecular and Xmal anomalies associated with disease
- -diagnosis, prognosis
- -monitor remission and relapse
- -must have baseline
- molecular diagnostics
- cytogenetics (karyotype and FISH)
what is a constitutional finding?
either karyotype or genotype
- original DNA and Xm complement that is foundation for genetic constitution in all cells of body
- originated in zygote
what are acquired anomalies?
change in constitutional DNA or karyotype
-usually present in a single cell line (clone)
what do unique VS non unique Xm rearrangements mean?
unique = specific diagnosis
not unique = general diagnosis
what is the link between Down syndrome and leukemia?
have 10-15x increased leukemia rate b/c third Xm 21 had RUNX1 (AML1)
what is loss of heterozygosity?
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)
remission VS relapse
remission: treatment suppresses disease (no clinical symptoms)
relapse: Xmal or molecular abnormalities reappear
how is FISH better than karyotype analysis?
takes 18-24 hours, and much quicker with higher statistical significance than karyotype study
how is gene amplification related to breast cancer?
specifically HER-1/neu type breast cancer
-with gene amplification, responds to drug herceptin better than without gene amplification
