L7 Neoplasia II Flashcards
Cancer is the ___ leading cause of death in the U.S.
Second
What are the 7 major variables leading to cancer?
- Geography
- Environmental
- Age
- Race
- Acquired predisposing conditions
- Genetic predisposition
- Genetic/inherited factors
Geographic variation in incidence of cancer is though to stem from differences in ___.
Exposure (to environmental carcinogens)
What are agents that damage DNA increasing risk for cancer?
Carcinogens
What are some environmental risk factors for cancer?
- Tobacco
- Alcohol
- Obesity
- Occupational exposures
- Sunlight
- Radiation
- Sexual exposures
Frequency of cancer increases with age - why?
Rising accumulation of somatic mutations and decline in immune competence.
True or false - most cancers are familial.
False - most are sporadic.
What are the three general patterns of inheritance for cancer?
- Autosomal dominant cancer syndromes
- Autosomal recessive syndromes of defective DNA repair
- Familial cancers of uncertain inheritance
What are two examples of autosomal dominant cancer syndromes?
- Familial adenomatous polyps of colon
2. Familial retinoblastoma
What generally characterizes autosomal recessive syndromes?
Chromosomal or DNA instability
What is an example of an autosomal recessive syndrome?
Xeroderma pigmentosum
What are two examples of acquired predisposing conditions?
- Chronic inflammation
2. Chronic tissue injury (smoking)
Cancer is a ___ disorder caused by ___.
Genetic; DNA mutations
What are the 4 classes of normal regulatory genes that are targets of cell damage?
- Proto-oncogenes
- Tumor suppressor genes
- Genes that regulate apoptosis
- Genes involved in DNA repair
Describe the promotion of proliferation by oncogenes.
- Growth factors and cytokines affect proto-oncogenes.
- Proto-oncogenes code for cyclins D and E
- Cyclins D and E activate CDK 2, 4, 6
- CDK 2, 4, 6 phosphorylate Rb, which in its unphosphorylated form binds E2F, blocking transcription.
- Phosphorylated Rb releases E2F, which binds to DNA and advances the cell cycle
Describe the control of proliferation by oncogenes.
- DNA damage, oncogenic activation, and hypoxia stimulate p53.
- p53 stimulates CDK inhibitors
- CDK inhibitors inhibit CDK and prevent the phosphorylation of Rb
What are normal cellular genes whose products promote cell proliferation?
Proto-oncogenes
What are mutant or over-expressed versions of normal proto-oncogenes?
Oncogenes
Name the gene product and associated tumor of the oncogene: ABL
Tyrosine kinase
Chronic myelogenous leukemia
Name the gene product and associated tumor of the oncogene: C-MYC
Transcription factor
Burkitt Lymphoma
Name the gene product and associated tumor of the oncogene: ERB-2
Tyrosine Kinase
Breast, ovarian, gastric carcinoma
Name the gene product and associated tumor of the oncogene: RAS
GTPase
Colon, pancreatic, carcinoma
Name the gene product and associated tumor of the oncogene: L-MYC
Transcription factor
Lung cancer
Name the gene product and associated tumor of the oncogene: RET
Tyrosine kinase
Multiple endocrine neoplasia
Name the gene product and associated tumor of the oncogene: C-KIT
Cytokine receptor
GI stromal tumor
What is the most commonly mutated proto-oncogene in human tumors? (30% of all human tumors contain this mutated version)
RAS
What is the normal function of RAS?
Inactive: bound to GDP
Active: bound to GTP, stimulates downstream regulators of proliferation
True or false - tumor suppressor genes typically need both normal alleles to be damaged in order to lead to cancer.
True (proto-oncogenes typically only need one hit)
Name the gene product and associated tumor of the tumor suppressor gene: RB
Rb gene product
Retinoblastoma, osteosarcoma
Name the gene product and associated tumor of the tumor suppressor gene: p53
P53 gene product
Most human cancers, Li Fraumeni syndrome
Name the gene product and associated tumor of the tumor suppressor gene: BRCA1 and 2
DNA repair protein
Breast, ovarian (BRCA1 only)
What is the “governor of the cell cycle”?
RB
What is a key histological feature of retinoblastoma?
Flexner-Wintersteiner rosettes
What is the “guardian of the genome”?
p53
What is the most commonly mutated gene in cancers?
p53
p53 can normally trigger one of three processes in the face of stress - what are they?
- Quiescence
- Senescence
- Apoptosis
What happens in Li-Fraumeni Syndrome?
Patients inherit one defective copy of p53 in the germline, and only need one additional hit
What are the anti-apoptotic proteins?
BCL-2, BCL-XL
What are the pro-apoptotic proteins?
BAX, BAK
What does Bcl-2 do to promote cell survival?
Prevents leakage of cytochrome c
What does Bax do to promote apoptosis?
Channel opens to allow leakage of cytochrome c, which leads to activation of caspases
What initiates the extrinsic death-receptor pathway?
Fas/Fas-L and caspases 8 and 9
What is the function of telomeres normally?
Telomeres are short, repeat sequences of DNA at the end of the strands that shorten with each somatic cell duplication. Eventually, the cell cycle arrests and telomerase is used to stabilize the telomere length.
How does cancer take advantage of telomerase?
- Without p53, DNA with shortened telomeres may enter a bridge-fusion-breakage cycle.
- With telomerase, this can then lead to cancer.
___ of neoplasms is necessary for growth in order to provide nutrients and oxygen.
Vascularization
What induces angiogenesis?
VEGF
What inhibits angiogenesis?
Thrombospondin 1 (TSP-1)
Describe the process of metastasis.
- Adhesion to/invasion of basement membrane
- Passage through ECM
- Intravasation
- Interaction with host lymphoid cells
- Tumor cell embolus
- Adhesion to basement membrane
- Extravasation
- Deposit
- Angiogenesis
- Growth
___ mediate adhesion of epithelial cells; they are sometimes lost in cancer, leading to detachment.
E-cadherins
What are the 6 hallmarks of cancer?
- Evade apoptosis
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Sustained angiogenesis
- Limitless replicative potential
- Tissue invasion and metastasis
