Malignancies Flashcards
RAS activates this pathway
PI3K pathway
This pathway leads to progrowth metabolism (Warburg)
PI3K pathway
Activated by Ras
RAS activates this transcription factor which stimulates production of MYC and cyclins
BRAF
BRAF is activated by RAS and induces production of these 2
MYC and cyclins
BRAF is activated by Ras and induces production of this, which leads to pro-growth pathways
MYC
This is dysregulated in neuroblastoma
MYC
Proteins that cause progression through the cell cycle
Cyclins
Cyclins attach to and activate these
Cyclin dependent kinases (CDKs)
These attach to and activate cyclin dependent kinases (CDKs)
cyclins
These phosphorylate various proteins to produce growth, division, metabolic effects
Lose activity when the attached cyclin degrades
Cyclin dependent kinases (CDKs)
Two checkpoints in the cell cycle
Between G1-S progression and G2-M progression
This cyclin binds CDK4
Cyclin D
Cyclin D binds this CDK
CDK4
MYC stimulates this cyclin pathway
Cyclin D
This stimulates the cyclin D pathway
MYC
This is inactivated and allows S phase entry
Rb
Tumor suppressor gene that is lost in Familial Retinoblastoma
Rb
Translocation in mantle cell lymphoma
t(11:14) of cyclin D
Ras may be dysregulated by this type of mutation
Gain of function
This inhibits many proto-oncogenes
p53
Tumor suppressor gene that inhibits cyclin dependent kinase (CDK4-Cyclin D complex)
Often lost in melanoma
p16
p16 inhibits this
Cyclin dependent kinase (CDK4-cyclin D complex)
Tumor suppressor gene that is often lost in melanoma
p16
PTEN inhibits this
PI3K
This inhibits PI3K
PTEN
This inhibits E2F transcription factor
Rb
Rb inhibits this transcription factor
E2F
Is RAS active or inactive when phosphorylated?
Active
To prevent inappropriate growth, these immediately dephosphorylate the RAS-GTP to its inactive form
GAP proteins
Are tumor suppressor proteins
GTPase activating protein (tumor suppressor gene) that normally inactivates RAS:GTP –> GDP, and when lost causes neurofibromatosis 1
NF1
Tumor suppressor gene that inhibits PI3K/AKt signaling
PTEN (phosphatase and tensin homologue)
Autosomal dominant disorder involving loss of function mutation of NF1 (GAP)
Neurofibromatosis 1
Neurofibromatosis 1 is caused by this
Loss of function mutation of NF1 gene
Autosomal dominant disorder caused by a loss of function mutation in PTEN gene
Cowden syndrome
Cowden syndrome is caused by this
Loss of function mutation of PTEN gene
Endometrial carcinoma, breast carcinoma, thyroid cancer, hamartomatous intestinal polyps and hamartomatous skin lesions are features of this condition
Cowden syndrome
Active form of Rb tumor suppressor gene is this
Hypophosphorylated
This binds and inactivates E2F, a pro-growth transcription factor
Rb
Rb binds and inactivates this
E2F, a pro-growth transcription factor
E2F is this
Pro-growth transcription factor
Autosomal dominant condition involving the inheritance of one allele, so only one more cell needs a mutation to produce a tumor
Familial Retinoblastoma
Inherited loss of a p53 copy (one hit)
25x risk of malignancy by age 50
Sarcomas, adrenal carcinoma, breast cancer, leukemia
Li-Fraumeni Syndrome
Li-Fraumeni Syndrome is an inherited loss of this
A p53 copy
Sarcomas and adrenal carcinoma are characteristic of this condition caused by loss of p53 copy
Li-Fraumeni Syndrome
Tumor suppressor gene lost in colon cancer
APC
Part of WNT signaling pathway to stabilize beta-catenin, a co-transcription factor
Part of WNT signaling pathway to stabilize beta-catenin, a co-transcription factor
Lost in colon cancer
APC
APC is a tumor suppressor gene lost in this
Colon cancer
Tumor suppressor gene lost in signet ring cancer of breast and stomach
CDH1
Tumor suppressor gene that encodes E-cadherin adhesion molecule
CDH1
Tumor suppressor gene lost in renal cell carcinomas
VHL
Gain of function of these lead to neoplasia
Oncogenes
Loss of function mutations of these lead to neoplasia
Tumor suppressor genes
Often a single mutation of these is needed for neoplasia (dominant pattern of inheritance)
Oncogenes
Usually need loss of both genes of these for neoplasia (recessive pattern of inheritance)
Tumor suppressor genes
Growth promoting metabolic alterations
Cells enter preferential fermentative metabolism
Provides excess carbon macromolecules at expense of energy
Warburg effect
p53 is this type of apoptotic force
Pro-apoptotic
bcl-2 is this type of apoptotic force
Anti-apoptotic
This is over-expressed in follicular lymphoma
t(14;18)
bcl-2
Over-expression of this results in slow-growing, indolent tumors
Incurable because low proliferation
bcl-2
Proteins that form channels in mitochondrial membrane
Bax/Bak
Protein that binds bax/bak and prevents its dimerization
Results in no mitochondrial permeability
Bcl-2
This protein activates bax/bak and relocates to mitochondrion
Results in increased mitochondrial permeability and caspase activation
p53
Cellular immortality most often involves this mechanism
Telomere
Some cancers reactivate telomerase function, and this is one mechanism
loss of p53
Some cancers have intrinsic telomerase activity by this method
Retain stem cell population
New vascular supply is needed for tumors to grow beyond this
1-2 mm
This type of tumor environment promotes HIF-enabled transcription
Ischemic
This inhibits VEGF
Loss allows VEGF to promote vessel growth (tumor angiogenesis)
p53
Monoclonal antibody that inhibits VEGF
Bevacizumab
Bevacizumab inhibits this
VEGF
Prevents angiogenesis
Transcription factor activated in ischemic tumor environment that promotes transcription of VEGF
Hypoxia inducible factor (HIF)
Cell adhesion molecule that is often lost or suppressed to allow metastatic epithelial cells to detach from each other
E-cadherin
In normal cells, epithelial integrins bind this on the matrix
Laminin
In normal cells, these bind matrix laminin
Epithelial integrins
In cancer, this is lost, which usually binds matrix laminin
Allows cells to attach to remodeled matrix
Integrin
In cancer, matrix is induced to produce this
Allows cells to attach to remodeled matrix
Fibronectin
Morphological stromal reaction to invasion
Desmoplasia
In order to survive intravascular travel, metastatic cells use this coating for stability and evasion of surveillance
Platelet
2 complementary adhesion molecules that allow metastatic cancer cell implantation in bone
E-cadherin and osteoblast N-cadherin
Antigens on tumor cells which are not recognized as self-antigens
Neoantigens
Tumor cells upregulate this which inhibits APCs
CTLA-4
Tumor cells upregulate CTLA-4, which inhibits this
APCs
2 proteins that tumor cells upregulate in order to inhibit/avoid T cell killing
CTLA-4 (inhibits APCs)
PD-L1 and PD-L2
Anti-CTLA-4 antibody
Ipilimumab
Ipilimumab is a monoclonal antibody against this
CTLA-4
Pembrolizumab and Nivolumab are antibodies against this
PD-1
Atezolizumab, Avelumab and Durvalumab are antibodies against this
PD-L1
Most frequently mutated gene in human cancer
p53
Normally p53 is inactivated by this
MDM2 ubiquitination
Protein that is normally inactivated by MDM2 ubiquitination
p53
Stressed cells have decrease MDM2 binding, which increases activity of this
p53
Stressed cells have decreased binding of this, which results in increased p53 activity
MDM2
This maintains Rb in active hypophosphorylated form
p21
p21 maintains this in active hypophosphorylated form
Rb
p53 increases activity of this CDK-inhibitor which maintains Rb in active hypophosphorylated form
p21
p53 can increase transcription of this to increase mitochondrial permeability and induce apoptosis
BAX
Tandem nucleotide repeats, normally of uniform constant length
Hallmark of loss of mismatch repair enzymes
Microsatellite instability (MSI)
Microsatellite instability (MSI) is hallmark of this
Loss of mismatch repair enzymes
Syndrome of defective MMR enzymes
Lynch syndrome
System to excise and correct pyrimidine residues cross-linked by UV radiation
Nucleotide excision repair
Disorder of NER enzyme loss of function (defect in components of excision repair)
HIGH rates of UV induced skin cancers (Squamous cell and Basal cell)
Xeroderma Pigmentosa
Repair of double stranded DNA breaks and DNA cross-links
Homologous recombination
Condition caused by Mutations/defects in Homologous recombination factors
Aplastic anemia, leukemia
Fanconi anemia
Cells that normally break and rejoin DNA, and errors in this produce frequent translocations
Lymphoid cells
Translocation in Burkitt Lymphoma
t(8:14)
Translocation of t(8:14) is characteristic of this
Burkitt Lymphoma
Translocation of t(14:18) is characteristic of this
Follicular lymphoma
Translocation of t(11:14) is characteristic of this
Mantle cell lymphoma
Translocation in Follicular Lymphoma
t(14:18)
Translocation in Mantle Cell Lymphoma
t(11:14)
Chemical carcinogen that preferentially causes specific mutation in TP53 codon 249
Aspergillus aflatoxin
Aspergillus aflatoxin results in this condition
Hepatocellular carcinoma
Hepatocellular Carcinoma can be caused by this chemical carcinogen
Aspergillus Aflatoxin
Aflatoxin preferentially causes this specific mutation
TP53 codon 249 (G:C –> T:A)
Type of specific UV radiation that produces pyrimidine dimers, especially T-T pairing
UV-B (280-320 nm)
Acute myeloid leukemia and Thyroid malignancies can be produced from this
Ionizing radiation
Infection that infects B cells via CD21 (complement receptor)
EBV
EBV infects these cells
B cells
EBV infects B cells via this
CD21, complement receptor
Infection that binding produces viral encoded proteins, LMP-1 and EBNA-2
EBV
Viral encoded proteins produced from EBV infecting B cells via CD21
LMP-1 and EBNA-2
Viral encoded protein with stimulated CD40 activated form that mimics helper T cell signaling, leading to B cell proliferation; also activates bcl2 and prevents apoptosis
LMP-1
The viral encoded protein LMP-1 results in these 2 main actions
B cell proliferation
Prevents apoptosis
Viral encoded protein EBNA2 activates this
Cyclin D1 (leads to proliferation)
Viral encoded protein that activates Cyclin D1, leads to proliferation
EBNA2
EBV results in polyclonal B cell proliferation, and this condition
Infectious Mononucleosis
What most commonly causes infectious mononucleosis?
EBV infection
Infectious mononucleosis involves proliferation of these cells as a result of EBV infection
Polyclonal B cell proliferation
EBV infection in patient with deficient immune system increases likelihood of this
t(8:14) = Burkitt lymphoma
This type of infection in patient with deficient immune system increases likelihood of t(8:14), leading to Burkitt Lymphoma
EBV
Microbial infection that can cause adult T cell leukemia/lymphoma
HTLV1
Microbial infection that can cause mucosal squamous cell carcinomas
HPV 16/18
Microbial infection that can cause gastric carcinoma and gastric MALT lymphoma
H. pylori
Microbial infection that can cause hepatocellular carcinoma
Hep C and B
Microbial infection that can cause nasopharyngeal carcinoma
EBV
Microbial infection that can cause B cell lymphomas in immune suppressed patients
EBV
These tumors often are functional
Endocrine
Parathyroid adenoma secretes these hormones
Prolactin, ACTH
Adrenal tumor secretes these hormones
Catecholamines (epinephrine)
Pancreatic tumor secretes this
Insulin
Signs and symptoms due to tumor but not explained by mass or function of tissue of origin
Paraneoplastic syndromes
Hypercatabolic state not explain by low caloric intake
Fat and muscle loss
Most often with advanced cancers
Thought to be due to TNF; other inflammatory mediators
Cancer Cachexia
A category used to predict behavior based on the tumor morphology
Sometimes uses Degree of Differentiation
Tumor grade
An assessment of the extent of tumor spread
Tumor stage
What is tumor grade?
Category used to predict behavior based on the tumor morphology
What is tumor stage?
Assessment of the extent of tumor spread
(describes what the tumor has already done)
3 components of tumor stage
T = primary tumor spread (tumor size, invasion of specific structures, vascular invasion)
N = are lymph nodes involved
M = metastases beyond lymph nodes
