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Foundations 1 > Week 4 > Flashcards

Week 4 Flashcards

1
Q

What are 2 ways epigenetics underpin genetic diseases

A

Pathogenic variant alterns chromatin directly and affect gene expression OR variant in a specific gene involved in chromatin regulation alters chromatin indirectly through an altered protein intermediate (gene expression vs epigenetic machinery)

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2
Q

how does histone modification impact chromatin

A

acetylation adds a negative charge, making it more open; deacetylation makes it more closed because it removes acetyl groups allowing the DNA to pack together more tightly, making it less accessible, decreasing rate of transcription etc

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3
Q

how does DNA methylation impact chromatin

A

methylation closes the DNA, demethylation opens

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4
Q

heterochromatin vs euchromatin

A

hetero is repressed/closed while eu is open/accessible

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5
Q

TADS

A

topologically assoc. domains; spatial segregation of chromatin, insulates genes so controlled by certain promoters etc

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6
Q

development path of differentiated cells

A

fertilization to implantation is demethylation (making them all baseline same) and then implantation to embryo is methylation (differentiate)

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7
Q

waddington model

A

cells go down a hill from progenitor to differentiated

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8
Q

HBB related to epigenetics?

A

pathogenic variant in TATA box; so TBP (binding protein) does not recognize TATA for transcription –> reduced HBB expression (gene expression)

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9
Q

fragile x syndrome related to epigenetics?

A

repeat in FMRI –> increased methylation –> no RNA expression/no FMRP protein (gene expression)

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10
Q

congenital limb malformation related to epigenetics

A

deletion of TAD –> overexpression of some genes (gene expression)

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11
Q

Kabuki syndrome

A

MLL2 and KDM6A both genes facilitate open structures in different ways; when mutated it is closed so gene expression goes down. MLL2 is a histone methylase and KDM6A is a histone demethylase (indirect by impacting protein)

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12
Q

fascloscalpulonumeral muscular dystrophy (FCMD)

A

normally DZ4Z repeat leads to closed chromatin and DUX4 not expressed. in mutant, 95% of disease, many repeats —> DUX4 expressed –> disease. in 5% of cases, caused by de novo variant in SMCHD I, normal number of repeats but a decreased methylation –> increase in DUX4.

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13
Q

imprinting

A

not all genes expressed from each chromosome

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14
Q

maternally imprinted

A

gene from maternal is NOT expressed

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15
Q

paternally imprinted

A

gene from paternal is NOT expressed

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16
Q

unipaternal disomy

A

inheritance of both homologs from a single parent; non disjunction in meiosis I; heterozygous because alleles are different even though from same parent

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17
Q

isodisomy

A

no homolog received from one parent, so other homolog is duplicated. homozygous, two identical homologs from same parent

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18
Q

UPD can unmask ____ alleles

A

recessive

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19
Q

PWS region

A

paternally expressed

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20
Q

AS region

A

maternally expressed

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21
Q

Prater willis syndrome

A

PWS not functioning. (PWS is turned on from dad and AS expressed is from mom) caused by deletion of paternal; maternal uniparental disomy; variant in imprinting control of paternal

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22
Q

angelman syndrome

A

maternal expression of UBE3A not working. caused by deletion of maternal, paternal uniparental disomy, imprinting variant on maternal, mutation of UBE3A on maternal allele

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23
Q

multistage carcinogenesis

A

normal colon (APC mutation) –> mucosa at risk (RAS overactivation) –> adenomas (loss of p53) –> carcinoma

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24
Q

3 stages of carcinogen

A

initiatior (reversible, DNA damage in gene, carcinogenic dose); promotor (enhances cell proliferation; reversible); progression (genetic mutation accumulates; benign becomes malignant; invasive metastatic tumor)

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25
Q

direct acting carcinogen

A

A small number of carcinogens do not require metabolic conversion (referred to as ‘metabolic activation’) to become carcinogenic. Most are weak carcinogens but are clinically important because some are cancer chemotherapeutic drugs (e.g., alkylating agents) that have cured, controlled or delayed recurrence of certain types of cancer (leukemias, lymphomas, ovarian cancer) only to later evoke a second form of cancer, usually acute myeloid leukemia. These are called direct-acting carcinogens. Examples: nitrogen mustards, nitrosomethylurea, cyclophosphamide and benzyl chloride.

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26
Q

indirect acting

A

Most chemical carcinogens require metabolic activation to an “ultimate carcinogen” before becoming active. Most of the known carcinogens are metabolized by the cytochrome P450-dependent mixed function mono-oxygenases. Chemicals requiring metabolic activation are known as indirect-acting carcinogens. The ultimate carcinogens are the electrophilic derivatives that actually initiate the neoplastic event.

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27
Q
  1. Explain genetic events or mutations which are believed to occur during human colon carcinogenesis.
A

When a clinical carcinoma arises, many mutations may be present in the tumor cells. Mutations often found in human colon cancers include APC loss, K-Ras activating mutations, Loss of heterozygosity of tumor suppressor genes such as TP53, mutations of Telomerase and many other genes. The mutations may likely occur in a stepwise manner and lead to progression through stages from increased growth, to benign tumors and finally to malignant tumors.

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28
Q
  1. How would you design an experimental protocol to test whether a given compound (chemical) is a tumor promoter or tumor initiator with skin?
A

A tumor initiator has the property that it induces permanent DNA damage, but is not alone sufficient for tumor formation. A tumor promoter enhances proliferation of initiated cells, but is reversible and does not affect DNA directly and is not alone sufficient to induce tumors. Either initiator or promoter alone will not induce tumors. For tumor induction, an initiator must be applied first, followed by a promoter sufficient to cause proliferation of the initiated cells leading to the development of a tumor.

29
Q
  1. How would one test to determine if a given compound is mutagenic?
A

The Ames test uses strains of Salmonella typhimurium bacteria that carry histidine synthesis mutations. The bacteria are exposed to the test compound and are spread on an agar plate. The bacteria initially grow and have the opportunity to mutate in the presence of a small amount of histidine. The mutagenicity of the substance is proportional to the number of colonies that grow when the histidine is later removed. The test can be modified to make it more relevant to the mammalian physiology by adding rat liver enzymes to replicate the effect of mammalian metabolic processes on the compound being tested.

30
Q
  1. What is the basis for dividing chemical carcinogens into direct and indirect-acting groups?
A

Direct carcinogens do not require metabolic activation to be carcinogenic. Cancer chemotherapeutic alkylating agent drugs are examples which can cause secondary cancer in treated patients. Indirect-acting carcinogens refer to chemicals that require metabolic activation to become active carcinogens. Polycyclic hydrocarbons formed by incomplete combustion of fossil fuels are examples of potent indirect-acting chemical carcinogens.

31
Q
  1. What are some mechanisms by which chemical carcinogens may lead to development of a malignant neoplasm?
A

Carcinogens may induce increased cell proliferation, loss of cell cycle checkpoint control and loss of normal apoptosis regulation. Carcinogens can have direct effects on regulatory genes within the susceptible cell and may also perturb normal immune surveillance

32
Q

Benzoyapryene

A

example of indirect acting carcinogen; metabolized by P450 and activated; forms adduct with guanine in DNA; from cig smoke; induce tumors (mutate RAS, inactivate P53 which senses cell damage)

33
Q

Alfatoxin B

A

indirect acting carcinogen, naturally occurring agent produced in mold. Aflatoxin B1 produces mutations in the p53 gene, and in regions where high dietary levels of aflatoxin B1 are consumed, 90% or more of mutations that develop in individuals with hepatocellular carcinoma are a characteristic G:C to T:A transversion in serine codon 249.

34
Q

what are the different levels which genetic disorders can be treated

A

gene – gene editing, gene replacement; mrna – ASO, siRNA; protein – protein replacement, folding of mutant protein; enhance mutant function; pathway – diet, biologics, enhance mutant function; family – genetic counseling

35
Q

gene replacement – how does it work, ex vivo vs in vivo, example

A

introduction of active gene in cell to make functional protein; ex vivo – gene added to vector and transduced into patient’s stem cell, modified cells infused with patient; all new cells made will carry this gene; vs in vivo – viral vector w transgene inserted straight into patient; gene goes to specific differentiated cells and not integrated into DNA; beta thalassemia

36
Q

what does ASO do

A

antisense oligonucleotide – as a small single stranded DNA that can bind to mRNA and mediate it (target splice sites, mutations, prevent translation, degradation etc) it can increase or decrease protein for LOF or GOF as needed

37
Q

examples of ASO

A

dravet, SMA

38
Q

RNAi and siRNA

A

RNAi regulates mRNA stability and translation; siRNA – can degrade mRNA coding for specific disease genes, thus silencing the mRNAs

39
Q

genetic treatment for beta thalassemia

A

gene editing/addition. CD34 stem cells transduced with lentiviral vector with the B globin gene so body will make RBC with hemoglobin; gene addition therapy; or genome editing using crispr/cas9 to break DNA, use NHEJ to insert erythroid (RBC) enhancer region to BCLII4

40
Q

genetic treatment for dravet

A

AOS. the variant in SCN1A causes protein to decrease. bc the NMD poison exon causes premature stop; so AOS prevents exon from being included, and thus no stop and protein levels increase

41
Q

genetic treatment for primary hyperoxalurias

A

siRNA. glyoxalate makes oxalate through LDHA. siRNA removes LDHA transcript in mRNA

42
Q

genetic treatment of duchenne

A

LTB4 when cleaved, releases TGFB which causes disease progression. so the antibody block cleavage from happening.; Anxa6 mediates repair; so a recomb. annexin A6 is added in to enhance repair

43
Q

cancer

A

uncontrolled abnormal growth of cells

44
Q

neoplasm

A

tumor, clonal uncontrolled growth

45
Q

neoplasia

A

unregulated clonal proliferation of abnormal cells/new growth

46
Q

dysplasia

A

disordered growth, used to describe tissue

47
Q

characteristics of benign tumor

A

well differentiated (looks like the tissue of origin), slowly expanding evenly, don’t invade other tissue, no metastis (spread to distant site)

48
Q

characteristics of malignant tumor

A

irregular shape, necrosis (dead cells), abnormal cells, tissue invasion, mestasis, poorly diff (doesnt look like tissue of origin)

49
Q

pass G1 checkpoint when

A

growth factors, nutrients, cell size

50
Q

DNA damage checkpoint – where is it, what is it checking?

A

in S phase, does chromosome and genome look normal?

51
Q

pass G2 checkpoint if

A

cell size, chromosome successfully replicated

52
Q

pass M checkpoint if

A

all chromosomes are attached to mitotic spindle

53
Q

what does RB do

A

gatekeeper into S phase, must be inactivated during G1 to allow E2F to begin

54
Q

what does P53 do

A

gatekeeper against cancer, dna damage sensor, leads to arrest, apoptosis, repair (p21)

55
Q

what are tumor suppressors

A

prevent abnormal cell growth, cause cancer through their LOF, eg. RB, p53

56
Q

what are protooncogenes

A

promote normal cell growth, cause cancer through GOF, eg MYC – transcription factor to master all the cell dividing etc activities; so when mutated it is always on and cell constantly dividing etc

57
Q

how are mutations accumulated

A

stepwise, often becomes cancer when there is a MYC or p53 variant

58
Q

how are cancer predisposition syndromes caused

A

germline genetic variants that increase the burden of somatic mutations; basically accumulating mutations more frequently

59
Q

what is the 2 hit hypothesis

A

to cause cancer, tumor suppressor genes need 2 hits (or 2 LOF mutations); in inherited cancer syndromes, when you get one from your family, you only need 1 more

60
Q

BRCA 1/2 do?

A

key factors in dna double strand break repair

61
Q

what does MLH 1 MLH2/6 do

A

key factor in DNA mismatch recognition/repair

62
Q

cancer predisposition syndrome with TP53 variant

A

li fraumeni syndrome

63
Q

cancer predisposition syndrome with RB1 variant

A

retinoblastoma

64
Q

cancer predisposition syndrome with hereditary breast/ovarian cancer

A

BRCA 1/2

65
Q

cancer predisposition syndrome with MLH 1 variant

A

hereditary nonpolyposis correctal cancer

66
Q

tumor testing

A

testing for SOMATIC changes, genome of the tumor itself, identify tumor subtype, prognostic information

67
Q

germline testing

A

testing for GERMLINE mutations, prophylatic surveillance, info on cancer risk

68
Q
  1. A 62-year-old man has had hemoptysis and a progressive cough for almost 2 months. An infiltrative lung mass is identified on imaging and a biopsy demonstrates non-small cell bronchogenic carcinoma. Molecular analysis identifies a p53 mutation. Which of the following mechanisms most likely contributed to neoplastic transformation?
    a. Activation of growth factor receptors
    b. Microsatellite instability
    c. Transcriptional activation
    d. Loss of cell cycle arrest
A

Loss of cell cycle arrest – p53 is a tumor suppressor gene that normally arrests the cell cycle in the late G1 phase when DNA damage occurs to allow for DNA repair or cell death. Loss of p53 (through mutation) prevents the cell cycle arrest and allows cells with DNA damage to continue to proliferate and divide.

69
Q
  1. A study was performed on biopsies of colon lesions that suggested evolution of a sporadic colonic adenoma into an invasive carcinoma. Which of the following descriptions best explains the mechanism involved in the development of the invasive carcinoma?
    a. Extensive regeneration of the cells leading to increased mutation rate
    b. Inheritance of defects in TP53 genes increasing the susceptibility to cancer
    c. Overexpression of growth factor receptor genes
    d. Stepwise accumulation of multiple mutations in proto-oncogenes and tumor suppressor genes
A

d. Stepwise accumulation of multiple mutations in proto-oncogenes and tumor suppressor genes
Extensive regeneration of the cells (a) and overexpression of growth factor receptor genes (c) can both contribute to cancer development, but are not sufficient changes for cancer development. The development of an invasive carcinoma in the colon requires the accumulation of mutations in proto-oncogenes and tumor suppressor genes. The inheritance of TP53 defects also contributes to multiple cancers, but is not associated with the development of sporadic colonic adenomas.

Foundations 1 (5 decks)

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