10 Molecular Basis of Cancer I Flashcards
Approximately how many mutations are needed to produce a cancer?
Multiple (5-7?)
No single mutation is sufficient to yield a malignant phenotype
If tissue cells have a maintained structure and organized growth, what are the characteristics of tumor cells?
Loss of tissue structure
invasion into adjacent tissue
continued growth
What is the size of the minimum detectable tumor?
What is the maximum tumor load compatible with life?
Min: ~1gm = 10^9 cells
Max: ~1kg = 10^12 cells (10 additional cell mass doublings)
What is the elapsed time to 10^9 cells (min. detectable tumor) for a single transformed cell in culture?
For tumor initiation in vivo?
90 days in culture
10-30 years in vivo
Tumors only grow if the loss is less than the increase. What are the 4 routes of tumor cell loss?
host defenses
terminal differentiation
shedding
necrosis
What is the basic flow diagram for cancer?
Normal cell -> Acquired DNA damage (chemical, radiation, virus) -> Either growth arrest/cell death OR failure of DNA repair -> Mutations in genome -> Expression of altered gene products and loss of regulatory gene products -> Clonal expansion, additional mutations, heterogeneity -> Malignant neoplasm
How are oncogenes neoplasia-associated genes?
Dominant/recessive inheritance?
Basis for familial cancer syndromes?
Provides cell with positive function
Dominant inheritance - only one copy needed
No basis for familial cancer syndromes
How are tumor suppressor genes neoplasia-associated genes?
Dominant/recessive inheritance?
Basis for familial cancer syndromes?
Loss leads to acquired cancer phenotype
Recessive - both copies mutated or deleted
Yes, basis for familial cancer syndromes
How are genome maintenance genes neoplasia-associated?
Basis for familial cancer syndromes?
Loss leads to more rapid acquisition of mutations
Does not contribute to cancer phenotype directly
Yes, basis for familial cancer syndromes
T/F
Reconstitution of genome maintenance reverses the neoplastic phenotype
False. It does not. Inhibition of oncogene action or reconstitution of tumor suppressor activity eliminates the neoplastic phenotype
Proto-oncogenes are:
Normal cellular gene that turns into an oncogene thru mutation
Mechanisms for proto-oncogenes becoming oncogenes are:
-altered regulatory domain
-fusion with another peptide coding sequence to result in new unregulated function
-increased expression
duplication (amplification)
loss of promoter methylation
What are the 5 inherited cancer syndromes? What gene is affected?
Are they autosomal dominant or recessive genetically?
Autosomal recessive Retinoblastoma - RB Li-Fraumeni syndrome - p53 Familial adenomatosis/colon cancer - APC Breast cancer - BRCA1 Multiple endocrine neoplasia 1 & 2 - MEN1, RET
What is Knudson’s 2 hit hypothesis? How does it involve loss of heterozygosity?
Tumor suppressor gene mutations are recessive. Both alleles must be inactivated to exhibit the phenotype. If one allele is already lost the likelihood of development of cancer is much higher. In many cases, the mutant allele is duplicated or the wild type allele is deleted resulting in loss of heterozygosity.
T/F
Morphologically similar tumors can have distinct genetic markers that specify different treatments and prognoses
True
Genetic analysis is increasingly used in cancer diagnosis
T/F
There is tissue specificity of certain genes for certain cancers.
True
What is the flow diagram example for colorectal cancer with the gene mutation for each step?
Normal epithelium -> (loss or mutation of APC) -> hyperproliferative epithelium -> (loss of DNA methylation) -> early adenoma -> (mutation of Ras gene) -> intermediate adenoma -> (loss of tumor suppressor on chromosome 18q) -> late adenoma -> (loss of p53) -> carcinoma
What are the 3 malignant characteristics that are acquired by neoplasms over time?
accelerated growth
invasiveness
metastatic potential
What is the cause of continued gene alterations in a tumor?
Competing subclones, some with different mutations, divide. When a more advantageous mutation comes along, it predominates. The more aggressive subclones will outgrow others, but there is still heterogeneity within the tumor.
What do subpopulations of a tumor differ in?
Subpopulations differ in: growth rate karyotype invasion and metastatic ability hormonal responsiveness antineoplastic drug susceptibility
Are the following cancers examples of aggressive or not aggressive tumors?
- chronic lymphocytic leukemia
- prostate cancer
- basal cell carcinoma
These rarely become aggressive
What are the 7 characteristics of cancer?
genome instability self-sufficiency growth signals insensitivity to growth inhibition evasion of programmed cell death limitless replication potential sustained angiogenesis tissue invasion and metastasis
What are the causes of genome instability? What functions are lost?
Decreased DNA repair
Loss of response to DNA damage
damage sensors - DNA breaks and mismatch detection
damage response mechanism - cell cycle arrest, apoptosis, DNA repair
What does p53 induce?
DNA repair
cell cycle arrest in cells with DNA damage
cell death in cells with DNA damage
