Molecular Genetics and Cancer Biology Flashcards
___ genes negatively regulate cellular growth and play
a critical role in the normal processes of the cell cycle.
Tumor suppressor genes negatively regulate cellular growth and play
a critical role in the normal processes of the cell cycle. These genes are also important for DNA repair and cell signaling.
Loss of function of ___ of a tumor suppressor gene is typically required for carcinogenesis.
Loss of function of both copies (alleles) of a tumor suppressor gene is typically required for carcinogenesis.
This functional loss of alelles from TS genes can occur via 4 mechanisms: (4)
(1) ___ gene deletion,
(2) loss of one allele and ___ of the second allele,
(3) mutational events involving __,
(4) loss of one allele and ___ of the second allele, often involving DNA ___, which suppresses expression of the gene.
1) homozygous gene deletion
(2) loss of one allele and mutational inactivation of the second allele,
(3) mutational events involving both alleles,
(4) loss of one allele and epigenetic inactivation of the second allele, often involving DNA methylation, which suppresses expression of the gene.
The “two-hit” hypothesis was first proposed in cases of retinoblastoma, which required mutations in ___ for disease manifestation
The “two-hit” hypothesis was first proposed in cases of retinoblastoma, which required mutations in both alleles for disease manifestation
T/F: specific types of mutations in certain genes may not follow the two-hit rule and can function in a dominant negative capacity when mutated, inhibiting the function of the normal protein from the unaltered allele.
An example is when two or more of the same protein molecules act together (such as ___) as is the case for __
true
Dimerization
tp53
Alternatively, deletion or mutation of a single allele may result in insufficient protein production (___), resulting in an increased carcinogen susceptibility as in the case of the CDKN1B (p27Kip1) gene
Alternatively, deletion or mutation of a single allele may result in insufficient protein production (haploinsufficiency), resulting in an increased carcinogen susceptibility as in the case of the CDKN1B (p27Kip1) gene (Fero et al., 1998).
Oncogenes are positively associated with __ and are the mutated form of normal genes (__).
Oncogenes are positively associated with cellular proliferation and are the mutated form of normal genes (proto-oncogenes).
Two oncogenes that have been found to be overexpressed in a variety of cancers include __ and ___
MYC and MET
MYC encodes an __ product that is a transcription factor responsible for regulating __. Amplification of MYC is a frequent event in __, and expression of MYC in human prostate epithelial cells has been associated with___
MYC encodes an early response gene product that is a transcription factor responsible for regulating cellular proliferation. Amplification of MYC is a frequent event in prostate cancer, and expression of MYC in human prostate epithelial cells has been associated with immortalization
___ acts through a receptor encoded by the proto-oncogene MET
Increased expression of MET has been reported in ___ and is also more frequent in higher grade cancers (Pisters et al., 1997). ____ of the MET proto-oncogene may also result in constitutive activation of the MET protein in tumors associated with hereditary renal cell carcinoma
Hepatocyte growth factor acts through a receptor encoded by the proto-oncogene MET . Increased expression of MET has been reported in renal cell carcinoma and is also more frequent in higher grade cancers. Missense mutations of the MET proto-oncogene may also result in constitutive activation of the MET protein in tumors associated with hereditary renal cell carcinoma
Mechanisms by which a proto-oncogene can be converted to
an activated oncogene are via (1) ___ of the proto-oncogene resulting in an ____ of the gene product
(2) ______
(3) ________
Mechanisms by which a proto-oncogene can be converted to
an activated oncogene are via (1) mutation of the proto-oncogene resulting in an active form of the gene product, (2) gene amplification, and (3) chromosomal rearrangement.
Immunohistochemical staining of bladder cancer specimens has demonstrated ___ in more than half of papillary and invasive tumors
Immunohistochemical staining of bladder cancer specimens has demonstrated overexpression of MYC protein in more than half of papillary and invasive tumors
chromosomal structural rearrangements such as _____ can result in the formation of an ____ for example, genetic rearrangement leading to the fusion of a portion of the TMPRSS2 gene and the ERG oncogene in a large proportion of ___cancers
chromosomal structural rearrangements such as translocation events can result in the formation of an oncogene; for example, genetic rearrangement leading to the fusion of a portion of the TMPRSS2 gene and the ERG oncogene in a large proportion of prostate cancers
In cancer, activated oncogenes and inactivated tumor suppressor genes alter the balance between these signals so that ____ is continuously favored.
NET PROLIFERATION
___ are considered to be out of cycle in a reversible
state known as “G0, ” which is the ___ for most cells.
Quiescent cells
Default state
For cell proliferation: series of events resulting in (a) duplication of the ___ during the DNA synthetic phase (S phase), followed by (b) segregation of each genomic complement to each of ___, a process referred to as mitosis (M phase). These two critical phases are separated by two so-called “Gap” phases (__
and __.
cell genome
2 resulting daughter cells
g1, g2
The retinoblastoma susceptibility protein, RB1 (formerly pRb), plays a central role in controlling the ___, a decision point in late G1 beyond which an __ to divide is made.
R-POINT
IRREVERSIBLE COMMITMENT
The inappropriate, continuous proliferation of cancer cells is largely due to a ___, typically the result of functional ___ of the RB1 pathway (Pardee, 1989). RB1 gene mutations have been identified in approximately one-third of ___, and reintroduction of the RB1 gene into bladder carcinoma cell lines has been found to ____
R-POINT CONTROL
INACTIVATION OF THE RB1 PATHWAY
BLADDER TUMORS
INHIBIT CELL GROWTH
T/F Prostate carcinoma has not been as strongly linked to RB1.
true
T/F Renal carcinoma has not been clearly linked to RB1.
true
The temporal sequencing of events occurring throughout the cell cycle is affected by a highly conserved set of protein kinases termed __
cyclin-dependent kinases, or CDKs
The enzymatic activities of the CDKs are dependent upon a class of regulatory proteins called __, so named because their ___ are tightly linked to specific phases of the cell cycle, during which they physically associate with and activate the CDK enzymatic activitY
cyclins
ABUNDANCES
Another group of proteins termed cyclin-dependent kinase inhibitors (CDKIs) bind to and directly ___ or their activating phosphorylations
INHIBIT CDK ACTIVITY
CDKIs belong to either of two different classes, the ____ ,broadly acting, able to inhibit multiple cyclin-CDK complexes throughout the cell cycle (Clurman and Porter, 1998), whereas the ____ are more restricted in their activities, inhibiting CDK4 and CDK6-containing complexes; thus they are critical regulators of the R-point and the G1
despite its proximity, the INK4B gene was ruled out as the primary tumor suppressor at this site because it was not within the deletion interval.
Cip/Kip family
ink-4 GROUP
A study by Orlow et al. (1999) found that __ AND ___ of the ____ occurred frequently in superficial bladder carcinoma, but only those deletions that affect both the __ and __ genes, which are located at the same locus, correlated with a ____.
DELETION AND METHYLATION
P16
P16 AND P14
DECREASED SURVIVAL
inactivation of INK4A by ___ has been implicated in prostate cancer.
PROMOTER HYPERMETHYLATION
. The p16 protein binds to cyclin-dependent kinases 4 and 6 and inhibits their interaction with ___ that normally mediates passage through G1
phase of the cell cycle by phosphorylation of the ___ . The __ encoding p16 was initially found to be mutated and deleted in a wide variety of tumors including bladder and kidney
cyclin D1
rb1 PROTEIN
INK4A gene
The TP53 ___ protein is a key player in cell cycle checkpoints, responding to DNA damage by signaling ___ arrest and ___ of the damage. If the ___ cannot be repaired, TP53 may trigger cell death (apoptosis). TP53 is the most commonly mutated gene in cancer and plays a prominent role in GU malignancies. TP53 was also recently found to be the most commonly mutated gene in the mutational landscape of metastatic cancer
TP53 tumor suppressor protein
DNA damage
cell cycle arrest and repair of the damage
Three major pathways by which DNA methylation may result in ____ in human cancer include:
(1) inherent mutational effects of ___
(2) ___ effects of promoter methylation on gene transcription
(3) potential gene activation and induction of ___ by DNA hypomethylation
genetic dysregulation
5-methylcytosine
epigenetic effects
chromosomal instability
The primary Th1 cytokine is ___. Th1 responses are characterized by: __, __ and __ Th1 responses are involved in viral clearance and in antitumor immune responses. Th2 responses are associated with __ and __ and generally prevent an antitumor immune response. In bladder cancer, Th2 cytokines in the urine after BCG treatment portend a __ outcome
IL-12
IL-12, interferon γ and tumor necrosis factor (TNF) α
TH2 chronic inflammation and infection
worse
The innate immune response is driven by recognition of repeated patterns in pathogens called : ____
pathogen associated molecular patterns (PAMPs)
The innate system is more __ and does not contain cell types that can give rise to __.
more primitive
memory cells.
Although BCG does bind directly to bladder epithelium, the first immune cell involved in BCG responses is the __
the macrophage (“big eater”)
Macrophages and PMNs are both ___ involved in the early phases of an immune response. Although both have potent cytotoxic activity, only ___ can ingest pathogens and present antigens in the context of MHC molecules.
both innate immune cells involved in the early phases of an immune response. Although both have potent cytotoxic activity, only macrophages can ingest pathogens and present antigens in the context of MHC molecules.
CD8 T cells are specialized for ___; they evolved to destroy virally infected cells. CD4 T cells are complex and include a number of phenotypes (Th1, Th2, Tregs, and others). CD8 T cells are cytotoxic and are capable of killing nearly any ___ (including cells resistant to chemotherapy). Although B cells DO come from the ____, that is not how they got their name. They were discovered in chickens in an organ called the bursa of Fabricius. The B comes from the word ____
CD8 T cells are specialized for cytotoxicity; they evolved to destroy virally infected cells. CD4 T cells are complex and include a number of phenotypes (Th1, Th2, Tregs, and others). CD8 T cells are cytotoxic and are capable of killing nearly any target cell (including cells resistant to chemotherapy). Although B cells DO come from the bone marrow, that is not how they got their name. They were discovered in chickens in an organ called the bursa of Fabricius. The B comes from the word bursa.
.
____ secrete antibodies, which help to clear pathogens. They also differentiate into ___, which drive a stronger and faster secondary response on reexposure to a pathogen. The generation of antibodies to ___ is probably a negative event; it would be expected to lead to a faster clearance and a less robust antitumor effect.
b-cells
MEMORY B-cells
BCG
Th2 cells secrete (4), all of which generally inhibit a ____
IL4, 5, 10, and 13
inhibit a succesful tumor response
In prostate cancer, inflammation has been associated with the consumption of ____ .
CHARRED MEAT and its toxins
cytotoxic CD8 T cells are generally associated with a better prognosis, in kidney cancer the ___ relationship has been described. This is a puzzling finding, which is not well understood. In ___, a robust CD8 infiltrate is generally associated with an improved outcome.
OPPOSITE
BLADDER CANCER
____ are cell-surface proteins that attenuate CD8 T cell function.
IMMUNE CHECKPOINT MOLECULES
SIPULEUCEL-T vaccine targets the ____ in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.
antigen PAP
Expression PD1 on tumor-infiltrating CD8 T cells is associated with a ___.
___ of the ___ interaction with monoclonal antibodies restores CD8 T-cell function, leading to tumor destruction (and shrinkage) in a minority of treated patients.
of PD-1
nonfunctional, exhausted phenotype
BLockage of the PD-1/PD-L1
____ of either PD-1 or PD-L1 is effective in bladder cancer in the second-line setting (as compared with chemotherapy). The overall response rate to these agents is in the range of ___.
BLOCKAGE
20-25%
Combined immune checkpoint blockade with antiPD-1 (____) and anti-CTLA-4 (___) is an approved first-line therapy for ___. It is more effective than treatment with the TKI ___, as evidence by improved overall survival and progression-free survival. However, it is also considerably more toxic, with___ adverse events being reasonably common.
NIVOLUMAB
ipilimumab
CLEAR CELL RC
Sunitinib
ENDOCRINE RELATED adverse events
Identify the gene and chromosme involved :
Phosphorylation is the attachment of a ___ to a protein. It alters the conformation of the protein and therefore is an excellent method of ___ function. ___ complexes phosphorylate RB1 or its family members, p107 and p130. Phosphorylated RB1 can ___ bind to members of the E2F family of transcription factors.
Phosphorylation is the attachment of a phosphate to a protein. It alters the conformation of the protein and therefore is an excellent method of regulating gene function. Cyclin-cdk complexes phosphorylate RB1 or its family members, p107 and p130. Phosphorylated RB1 can no longer bind to members of the E2F family of transcription factors.
DNA damage can lead to cell cycle arrest at both the __ and __ checkpoints
G1S and G2M checkpoints.
___ is a major defense against DNA damage caused by __ and chemical exposure. ___ is the primary mechanism for repairing damage caused by ___. ____ is the primary mechanism for polymerase errors. ____ is the primary mechanism for repairing double-strand breaks.
Nucleotide excision repair (NER) is a major defense against DNA damage caused by ultraviolet radiation and chemical exposure.
Base excision repair (BER) is the primary mechanism for repairing damage caused by reactive oxygen species.
MMR is the primary mechanism for polymerase errors. Double-strand break repair is the primary mechanism for repairing double-strand breaks.
____ is one of two mechanisms for repairing DNA double-strand breaks, the other being ___homologous end joining (NHEJ). In HR, the normal undamaged __ is used as a template to repair the damaged segment of DNA.
Homologous recombinations (HR)
NON-Homologous end joining (NHEJ)
SISTER Chromatid
The TP53-induced apoptosis is dependent on the ___
The TP53-induced apoptosis is dependent on the APAF-1/caspase 9 activation pathway.
Although each proapoptotic bcl-2 family member responds to different stimuli, the principal mechanism by which these family members induce cell death is by :____
Although each proapoptotic bcl-2 family member responds to different stimuli, the principal mechanism by which these family members induce cell death is by increasing mitochondrial membrane permeability.
Telomerase immortalizes cells by maintaining the ends of the chromosomes, or ___, which normally ___ with each cell division.
TELOMERES
SHORTEN
Normal cells closely monitor their telomere lengths and, should they fall below a critical ___ length, will initiate either cell __ or __. If key players in these responses (e.g., TP53) are mutated, then chromosomal instability may result in contributing to __. To date, there is a strong/not a strong connection known for telomere loss and loss of DNA methylation.
Normal cells closely monitor their telomere lengths and, should they fall below a critical threshold length, will initiate either cell senescence or apoptosis. If key players in these responses (e.g., TP53) are mutated, then chromosomal instability may result contributing to cancer initiation. To date, there is not a strong connection known for telomere loss and loss of DNA methylation
The urologic malignancy most closely linked to a karyotypic abnormality is a ___ tumor. A ___ was first identified in a testis tumor in the 1980s, and experimentally this cytogenetic hallmark of testicular tumors has diagnostic and prognostic value.
TESTIS
12P-Chromosome
Systematic review of GWAS studies in prostate cancer indicate that the ____ continues to be the most implicated in prostate cancer risk, and among different racial cohorts.
8Q24 region
Direct interactions between the ___ , ___ and genitourinary cancer development or progression is now an area of active study.
urinary microbiome, GI microbiota
