Flashcards in 03/02d Neoplasia III Deck (27)
What is clonal expansion?
The idea that all the cells in a tumor or cancer are derived from a single cell
This is confirmed by the fact that all cells maintain the earliest genetic alteration that lead to cancer
Why do tumor cells have so many mutations?
They must change to evade the immune system, develop metastasis, and initiate angiogenesis
What is the progression of genetic mutations in HNPCC?
1) Mutations in tumor suppressors - APC/beta-catenin, FAP
2) Mutations in oncogenes - FAS/BRAF, 18q
3) Mutations in chromosomal or microsatellite genes (caretaker genes) - p53, PIK3CA
What gene functions can be altered in cancer? Name seven
1) Oncogene activation - self-sufficient from growth factor
2) Inactivation of tumor suppressor genes - ignore inhibitory signals
3) Evasion of apoptosis
4) Defects in DNA
5) Expression to telomerase - limitless replicative potential
6) Sustained angiogenesis
7) Ability to invade and metastasize
What genetic mechanisms can occur to activate oncogenes or inactivate tumor suppressors?
1) Mutations, and disruptions by viruses
2) Genetic amplifications, usually of areas containing oncogenes
3) Deletion of tumor suppressor genes
4) Translocations, often of chromosome segments
What are protooncogenes? What is their relationship with oncogenes?
Protooncogenes are normal cellular genes which are involved in growth regulation (growth factors, growth factor receptors, growth signal pathways, etc.)
When protooncogenes are activated in specific ways, they become oncogenes and lead to unrestricted growth
What is SRC?
A gene that is acquired from host cells by Rous sarcoma virus when it integrates into the host genome
Functions to stimulate host cells to divide, and thus spread more virus
What is c-SRC? What is v-SRC?
c-SRC is a proto-oncogene, which functions in controlling cell division and has an inhibitory site at its C-terminal
v-SRC is an oncogene, which lacks the inhibitory site found on c-SRC and is thus constitutively active, which leads to inappropriate cell division
What is the most common oncogene found in human cancers?
What does Ras code for?
A protein that binds GTP and degrades it to GDP
When mutated, Ras encodes a constitutively active protein which continually transduces signals for cell growth
What are five oncogenes which are commonly amplified in human cancers?
Cyclin D1 (CCND1)
What is a tumor suppressor gene?
A gene that slows cell growth, causes cell differentiation, activates apoptosis, or repairs DNA
What is the significance of amplified ERBB2?
Correlates with poor prognosis in breast cancer
Chromosomal translocation between Ch. 8 and Ch. 14 corresponds with what type of cancer?
Chromosomal translocation between Ch. 9 and Ch. 22 correspond with what type of cancer?
Chronic myelogenous leukemia
How many alleles do you need to activate an oncogene
How many alleles do you need to activate a tumor suppressor?
What is the function of Rb?
Controls the cell's transition from the G1 phase to the S phase of the cell cycle
How does Rb work?
Hypophosphorylated Rb binds to E2F (transcription factor) --> cell cycle does NOT progress
Hyperphosphorylated Rb does not bind to E2F --> cell cycle moves forward
What is TP53?
"The guardian of the genome"
Prevents replication of DNA which has been damaged
Mutated in more than half of human tumors
What happens if p53 is mutated?
The cell cycle isn't halted when DNA is damaged
Damaged DNA is passed on to new cells, which leads to accumulation of mutations
What are "gate-keeper genes"?
Tissue-specific cancer genes
Mutated at a very early stage of cancer initiation
What genes are often mutated in familial adenomatous polyposis?
APC/beta-catenin pathway proteins
What is the function of APC/beta-catenin pathway? What happens when it is mutated?
APC binds beta-catenin, which prevents the transcription of growth-promoting genes
Mutations in APC or catenin allow unregulated transcription of growth-promoters, which can lead to colorectal tumors
What are caretaker genes?
Genes which maintain genomic or stability by DNA repair or maintenance of chromosomal stability
Loss of function increases the risk of mutations in other genes, such as oncogenes and tumor suppressors
What is HNPCC?
Hereditary non-polyposis colon cancer
Occurs at a young age, and does not arise in polyps
Found in multiple direct family relatives
Due to mutations in DNA mistmatch repair genes