Cancer Flashcards
What are the steps involved in cancer transformation?
- 1st mutation acquired–selective growth of that cell line
- Additional mutations acquired, each providing a selective advantage
- expansion produces an increasingly unregulated/aggressive clone line
- Tumor
3 normal cell functions disrupted in a malignant transformation:
Repair
Growth
Cell-to-cell interactions
6 mechanisms involved in malignant transform:
Mutation Structural rearrangement Copy number changes Epigenetics miRNA telomerase
Explain the typical multi-step process of cancer development
Normal epithelium -> loss of TS drives hyperprolif
Activation of oncogene -> early adenoma
Continual loss of tumor suppressor genes -> cancer
*oncogene activation drives loss of suppressor
What changes accompany clonal expansion?
Genetic heterogeneity (from one starting cell, heterogeneous tumor cell variants)
What is characteristically unstable in tumors?
Heterogenous genomic instability
Oncogenes are growth (promoting/restricting)
Promoting
TS genes are growth (promoting/restricting)
Restricting
Oncogenes are associated with (gain/loss) of function mutations
Gain
TS genes are associated with (gain/loss) of function
Loss
What cancer is caused by RB1?
Retinoblastoma
What cancer is associated with MLH1, MLH2 and MLH6? What is dysfunctional if mutated?
Lynch syndrome
DNA repair
What is the relationship between TS genes and cancer?
Loss or inactivation of both TS alleles -> cancer
60% of retinoblastoma results from _______ mutations, in which both alleles are acquired
Sporadic
40% of retinoblastoma results from _______ mutations, in which one allele is acquired
Hereditary
Associated with constitutional heterogeneity in a tumor suppressor gene line
Hereditary mutations
T/F: Once a tumor is formed, mutation accumulation is no longer necessary.
F–tumor formation drives additional mutations
How do hereditary cancers caused by TS genes segregate?
Autosomal dominant with reduced penetrance
At the level of a patient with a hereditary TS-associated cancer, the phenotype is:
Dominant
At the level of a tumor in a hereditary TS-associated cancer, the phenotype is:
Recessive
Tumor cells are (hetero/homo)zygous mutants
Homozygous (they acquire a second mutation)
What occurs in the “2nd hit”?
Loss of the normal allele
Most common mechanisms of second hit (in terms of DNA segment loss)?
Microdeletion
Mitosis nondisjunction
Mitotic recombination
What are 3 ways that function of the normal allele is lost in 2nd hit?
- loss of heterozygosity
- Point mutations
- Epigenetic silencing
3 ways that oncogenes are activated?
point mutations (example: RAS) acquired reciprocal translocations gene amplification (100/s of copies in cell)
BCR-ABL fusion is associated with what disorder? How does this occur?
CML
Activates oncogene via reciprocal translation
How does imatinib treat BCR-ABL fusion?
Targets actual fusion protein
Explain gene amplification.
The tumor cell has hundreds of copies of proto-oncogenes, which confers a selective advantage
2 types of gene amplification
- HSR (homogeneously staining regions)
visiable as an extra non-banded region - DM (double minutes)
extrachromosomal, circular DNA lacking centromeres and telomeres
This type of gene amplification is associated with random segregation
DM
T/F: Extreme abnormal copy number variation is often present in tumors, but may also be constitutional
F: Never constitutional
Type of amplification common in breast cancers?
HER2 (an EGFR)
Chromosomal aberrations in cancer may lead to:
Aneuploidy (full or partial)
Apparently intact chromosomes (but with abnormalities)
What is involved in the multistep process of malignant transformation?
Multiple acquired (somatic) mutations
Clonal expansion of the altered cell lines
