Neoplasia I (markers, genes, proteins) Flashcards
What is an autocrine loop?
It is a feedback mechanism produced by some cancers cells by GFs they produce.
What GFs are typical of a glioblastoma to produce?
PDGF and PDGF receptor tyrosine kinases.
What GFs are typical of a sarcoma to produce?
TGF-alpha and EDGF
Hoe are receptor tyrosine kinases activated in tumor cells?
Via point mutations, gene rearrangements and gene amplification.
What is the function of ERBB1?
It encodes EGFR, which is involved by point mutations.
They are often found in a subset of adenocarcinomas of the lung.
Mutations cause constitutive activation of EGFR tyrosine kinases.
What is the function of ERBB2?
It encodes HER2, a receptor tyrosine kinase.
The gene is amplified in certain breast carcinomas, leading to overexpression.
What is the function of ALK, in terms of lung adenocarcinomas?
It is activated by a gene rearrangement. A deletion of chr. 5 fuses with EML4 in a subset of lung adenocarcinomas resulting in a EML4-ALK fusion gene.
Which RTKs are associated with lung adenocarcinomas?
ERBB1 or ALK
Which RTKs are associated with breast carcinomas?
ERBB2 and HER2
Generally, what stimulates RAS?
It is stimulated by RTKs and two “downstream” arms, the MAPK cascade and PI3K/AKT pathway.
________ mutations in ____ family genes constitute the most common type of abnormality involving proto-oncogenes in humans.
Point mutations in the RAS family genes.
Which cancers have a high association with RAS point mutations?
90% of pancreatic adenocarcinomas and cholangiocarcinomas
50% of colon, endometrial and thyroid cancers
30% of lung adenocarcinomas and myeloid leukemias
Several distinct RAS point mutations have been identified that reduce _____ activity of the RAS protein. What does this result in?
GTPase
Results in mutated forms of RAS being trapped in the activated GTP-bound form and cell is continuously receiving pro-growth signals.
Mutations in BRAF has been associated with?
100% of hairy cell leukemias
60% of melanomas
80% of benign nevi
What is the function of BRAF?
It is a ser/thr kinase that sits atop the cascade in the MAPK family. BRAFs activation causes downstream activation of kinases and TFs.
What can be given to patients with advanced melanomas?
BRAF inhibitors, and it shows significant promise
What is the function of PTEN?
It is a tumor suppressor gene whose function is lost through mutation or epigenetic silencing in many cancers, but commonly endometrial cancers.
What is an example of a mutation in a cytosolic tyrosine kinase?
ABL
What occurs in chronic myelogenous leukemia in terms of ABL?
The ABL gene is translocated from chr 9 to chr 22 where it fuses with the BCR gene. The resulting BCR-ABL tyr kinase is highly oncogenic.
Cytosolic tyrosine kinase word association:
CML –> BCR-ABL
What is the master TF regulator of cell growth?
MYC.
It is seen in the fastest growing tumors.
What malignancy should be associated with MYC?
Burkitt lymphoma
MYC responds to the:
Immediate early response genes, which are rapidly and transiently induced by RAS/MAPK signaling following GF stimulation.
How does MYC become oncogenic? (4)
- MYC activates expression genes involved in cell growth.
- In some contexts, MYC upregulates expression of telomerase.
- MYC can reprogram somatic cells into plurioptent stem cells.
- MYC is at least partially responsible for the Warburg effect.
Which 2 MYC proteins are amplified in neuroblastomas?
NMYC and LMYC
What do gain-of-function mutations in D cyclin and CDK4 cause?
It promotes progression from G1/S phases.
Amplification of CD4 genes occurs in which cancers? (3)
Melanomas
Sarcomas
Glioblastomas
Which tumor suppressor genes encode proteins to arrest cells at G1/S?
RB
TP53
CDKIs
How many defective RB genes are required to affect cell behavior?
Germline mutations occur in which inheritance pattern?
At the individual cell level, in what way does it behave?
2
AD
AR fashion
In what 3 ways can RB function (leading to malignancy) be compromised?
- Loss of function mutations involving both alleles.
- Shift from hypophosphorylated state (active) to hyperphosphorylated state (inactive) by gain of function mutations that upregulate CDK/cyclin D activity.
- Loss of function mutations in CDKIs.
RB mutations are associted with which 2 malignancies?
Retinoblastoma and Osteosarcoma
What is the high yield theory regarding retinoblastoma?
The two hit theory, meaning both alleles must be mutated.
How does retinoblastoma develop?
When the normal RB allele is mutated in retinoblasts (second hit) along with the inherited copy of a defective gene (first hit).
In somatic cases, how does retinoblastoma occur?
Both RB alleles must undergo somatic mutations because no mutant copies are inherited.
How does HPV lead to malignancy?
It neutralizes RB by expression of E7 which binds RB with high affinity.
This does not allow RB to bind E2F TFs and inhibit them. The cell cycle is allowed to continue.
What is the function of E6?
What cancers is it associated with?
It is another protein produced by HPV (in addition to E7) that degrades p53.
Cervical carcinoma and squamous cell carcinoma of head and neck.
How are TP53 mutations inherited?
What kind of job does it do?
AD and follows a two hit hypothesis
It is a tumor suppressor gene and stops neoplasia by inducing cell cycle arrest, senescence and apoptosis.
Which types of cells are more likely to be killed by chemo or irradiation: wildtype TP53 or mutant TP53?
Wildtype more likely to be killed.
Which cancers are more likely to die from irradiation or chemo due to ______ TP53?
Wildtype.
Testicular teratocarcinomas and acute lymphoblastic leukemia
Which cancers are more likely to be resistant to irradiation or chemo due to _______ TP53?
Mutant
Lung cancers and colorectal cancers
People with Li-Fraumeni syndrome have a 25x chance to malignant tumor by age 50 than general pop. What are the cancers?
SBLA Sarcoma Breast Leukemia Adrenal gland
What is the function of APC?
It is a tumor suppressor gene that, when mutated, allows activation of beta-catenin which causes unregulated proliferation.
APC loss of function mutations are associated with:
Inheritance:
What is the main cancer associated with its mutation?
Familial adenomatous polyposis
AD, pts. with one mutant allele develop thousands of polyps during teens and 20s.
NF’s function:
Loss of function mutations result in?
Negative regulator of RAS
Neurofibromas
PTCH function:
Germline mutations cause what?
Inhibits hedgehog pathway.
Gorlin syndrome which marks a high risk for basal cell carcinoma and medulloblastoma.
VHL function
Associated cancers:
Encodes a component of ubiquitin ligase which degrades hypoxia inducible factors.
Can lead to renal cell carcinoma and pheochromocytoma.
CDH1 mutations leads to:
GI carcinomas
Growth factor receptors to know? (2)
EGF receptor family
ALK RTKs
Proteins involved in signal transduction? (4)
RAS
ABL (non RTK)
BRAF
SHH/WNT
What are good prognostic indicators in children with neuroblastoma?
TRK neurotrophin receptor genes (A,B,C), which have a crucial role in growth, survival and differentiation of neural cells.
They are in the ALK group of RTKs.
Where were RAS genes (HRAS, KRAS, NRAS) initially discovered?
In transforming retroviruses.
What is oncogene addiction?
The phenomenon in melanoma where cells with only BRAF mutations respond to BRAF inhibitors.
What can result from mutations in HH?
Holoprosencephaly, cyclopia
What cancer has the closest association w/ HH signaling?
What other cancers are implicated?
Basal cell carcinoma.
Brain, lung, mammary gland, prostate and skin
How is it thought that HH can lead to tumors?
By transforming adult stem cells into cancer stem cells.
What is the most common malignant brain tumor of childhood?
What is this cancer associated with?
Medulloblastoma
WNT and SHH
MYC is expressed in all euk cells. What induces it? What follows it?
Induced by RAS/MAPK and follows GF stimulation of quiescent cells.
What are inhibitors of mitogenic signaling pathways and their inheritance? (4)
APC (AD)
NF1 (AD)
NF2 (AD)
PTCH
Inhibitor of cell cycle progression:
RB (AD)
Inhibitor of pro-growth programs of metabolism and angiogenesis:
VHL (AD)
Inhibitor of invasion and metastasis:
CDH1 (E-cadherin)
DNA repair factors (3)
BRCA1, BRCA2
MSH (AR)
Which protein works in an unknown fashion?
WT1
What is “the gatekeeper of colonic neoplasia”?
APC
What tumors are related to VHL? (4)
CNS tumors
Renal cysts
Neuroendocrine tumors
Renal cell carcinoma
Where is the RB gene located?
13q14
Loss of normal cell cycle control is central to malignant transformation and at least one of the following is dysregulated: (4)
p16/INK4a
cyclin D
CDK4
RB
What holds p53 at bay in normal cells (inhibits it)?
MDM2
In terms of p53, what happens in healthy cells when stressed?
p53 accumulates and binds DNA and activates p21 (CDKi) and GADD45 for repair or activates apoptosis or senescence.
In terms of p53, what happens when damaged cells?
p53 does not activate any repair genes or apoptotic genes and mutant cells can continue to divide.
What Abs can be used to boost immune response in cancer cells?
Abs targeted against PD-1 or PD-L1, to boost immunity.
What can be used to treat melanoma?
An inhibitor of CTLA-4 to boost immunity. It has more side effects than the PD-1 inhibitors.
What is the idea behind PDE4 as a therapeautic?
PDE4 degrades cAMP in WBCs.
Proinflammatory mediators (TNFa, IL-17, IFN-y) released by these cells occur due to cAMP.
cAMP may also promote production of anti-inflammatory cytokine like IL-10.
What is the idea behind PDE4 as a therapeautic?
What can it treat?
PDE4 degrades cAMP in WBCs.
Proinflammatory mediators (TNFa, IL-17, IFN-y) released by these cells occur due to cAMP.
cAMP may also promote production of anti-inflammatory cytokine like IL-10.
Psoriasis
What are 3 antitumor effector cells?
CTLs
NK cells
Mo
What do miRNAs do?
They helps regulate cell growth, differentiation and survival and play a role in carcinogenesis.
What are 2 common radiation induced cancers?
Myeloid leukemias
Thyroid cancer in young people
What cancers are relatively resistant to radiation-induced neoplasia? (3)
Skin, bone and GI tract.
What is an oncogenic RNA virus?
HTLV-1
What are some oncogenic DNA viruses? (5)
HPV EBV HBV Merkel cell polyomavirus (MCV) HHV-8
What are some clinical aspects of neoplasia? (4)
Cachexia
Paraneoplastic syndromes -endocrinopathies -hypercalcemia -neuromyopathies -acanthosis nigricans hypertrophic osteoarthropathy
Migratory thrombophlebitis
DIC
What is chemothripsis?
A phenomenon where tens to hundred of clustered rearrangements affecting one or more chromosomes in cancer cells.
Usually due to one catastrophic event.
the following mucins and glycoproteins are associated with which cancers?
CA-125
CA-19-9
CA-15-3
CA-125: ovarian cancer
CA-19-9: colon cancer, pancreatic cancer
CA-15-3: breast cancer
Carcinoembryonic antigen (CEA) is elaborated in which carcinomas?
Colon
Pancreas
Stomach
Breast
Alpha-fetoprotein is produced in what cancer primarily?
Hepatocellular carcinomas
PSA, CEA and AFP are most useful for:
Detection of recurrences after excision
HCG (human chorionic gonadotropin) is used as a marker for which tumor?
Testicular tumors
Ig or light chains are used as markers for:
Multiple myelomas or other secretory plasma cell tumors
Carcinoma vs. Sarcoma
Derived from:
How does it spread?
Does it have an in situ phase?
Carcinoma
Derived from: epithelium
How does it spread? Lymphatics
Does it have an in situ phase? Yes, carcinoma in situ
Sarcoma
Derived from: CT
How does it spread? Blood
Does it have an in situ phase? No
