Week 4 Flashcards
1
Q
inactived X chromosomes, seen in Kleinfelter syndrome
A
Barr bodies
2
Q
normal phenomenon where one of the 2 X chromosomes in every cell of a female individual is inactivated during embryonic development
A
lionization
3
Q
what percent of women have X inactivation ration
A
90%
4
Q
Why is the normal X chromosome inactivated in balanced X autosome translocation?
A
inactivation of X chromosome causes an imbalance of gene expression
5
Q
Sons of an affected male are usually unaffected in ____, while daughters are obligate carriers
A
X linked inheritance
6
Q
expressed in all males who receive mutation, can skip generation, no father to son transmission
A
X linked recessive
7
Q
CCG triplet expansion in 5’ FMR1 (gene not expressed), 56-200 repeats= unstable mutation, promoter silencing by CpG methylation= no FMR1 expression
anticipation DNA methylation and haplotype effect (arrangement of neighboring loci on the same chromosome)
A
Fragile X (XD with reduced penetrance)
8
Q
mutation in MECP2 gene (Xq28, methyl-CpG-binding protein-2), transcriptional silencing, and epigenetic regulation of methylated DNA
95% de novo mutations, almost exclusively in male germline
manifests after 6-18 months of age in females, men die in utero or after birth
Impairments in language and coordination and repetitive hand movements like wringing/squeezing or clapping/tapping, slower growth, difficulty walking, smaller head size, seizures, scoliosis, and sleeping problems
variable expressivity
A
Rett syndrome (XD)
9
Q
mutation in F8 (Type A) and F9 (Type B)
most cases of severe type A due to intron 22 inversion results in 2 incomplete transcripts
acute and recurrent hemarthrosis (bleeding into joints) and hematomas
with age, severity, and frequency of episodes increase
bleeds in brain are life-threatening
F9 expression increases by 1/3 at puberty
A
Hemophilia A and B (XR)
10
Q
X linked recessive + X inactivation:
Mutation in dystrophine gene
Large deletions (60-65%), large duplications (5-10%), small deletions, insertions, or nucleotide changes (25-30%)
33% de novo mutations
14% germline mosaicism → 7% reccurerence risk in apparent noncarrier mothers with affected child
Progressive degeneration of skeletal muscle, usually after a latency period of seemingly normal development and function (>2 yrs), difficulty in climbing stairs, frequent falls, and progressive difficulty in rising from floor are early features. Pseudohypertrophy of calves, mild mental retardation, cardiomyopathy (95%), 50-60% carrier females have cardiac abnormalities, and slightly elevated serum CK levels even in absence of other symptoms
A
Duschene Muscular Dystrophy
11
Q
X linked recessive
Mucopolysaccharidosis type II (MPS II), accumulation of glycosamingoglyicas (GAGs) in lysosome
Mutation is IDS= iduronate-2-sulfatase
break down of 2 ECM proteoglyvans, dematan sulfate and herpan sulfate is impared
Born normal then, abdominal hernias, ear infection, runny noses, colds, coarseness of facial features, prominent forehead, nose with flattened bridge, an enlarged tongue, large head, hepatosplenomegaly, aggressive behavior
A
Hunter Syndrome (XR)
12
Q
X linked recessive
Mutation in Bruton tyrosine kinase (BTK), stops B-cell maturation at pre-B cell stage. T cell immunity remains in tact
No antibodies in blood, newborns normal, present w/ lung infections, ear infections, pink eye, and sinus infection. Infections that cause diarrhea, Note: live attenuated vaccines could be dangerous because of no immune response (live polio, MMR)
A
Bruton Agammaglobulinemia
(aka X Linked agammaglobinulinemia XLA)
13
Q
X linked recessive
Incomplete penetrance in heterozygous female because random x inactivation
Mutation in a-galactosidase A → accumulation of glycolipid globotriaosylceramide in walls of blood vessels
Multisystem disorder (kidneys, heart, NS, skin, eyes), full body or localized pain to extremities (deposits in nerve fibers) or GI tract, angiokeratomas, proteinuria, kidney failure, cardiac hypertrophy, valve disease, anhidrosis, corneal clouding
A
Fabry Disease
14
Q
X linked recessive
Deficiency in HGPRT 1, overproduction of uric acid (hyperuricema)
Failure of purine salvage pathway = accumulation of breakdown product and stimulation of de novo synthesis pathway
Sand like crystals of uric acid in diapers, gout, kidney stones, bladder, ureter, hypotonia, aggressiveness, finger biting, patients poorly use vitamin B12 → megaloblastic anemia, death usually due to kidney failure or complications from hypotonia
A
Lesch Nyhan Syndrome
15
Q
X linked recessive
Mutation in GPR143 (OA1) product GPCR like protein localizes to melanosomes and involved in melanosomal biogenesis. Activation of OA1 receptor by L-DOPA → secretion of neurotropic factor by retinal pigment epithelium helps in normal retinal development
Reduced coloring of iris and retina (ocular hypopigementation, eye appears blueish pink); foveal hypoplasia, rapid involuntary eye movement (nystagmus), poor vision and depth perception, increased sensitivity to light
Astigmatism and lazy eye/strabismus
A
Ocular Albinism
16
Q
X linked recessive
OTC deficiency, failure to convert carbon phosphate to citrulline, most common urea cycle disorder → hyperammonemia
Male infant by the second day of life becomes irritable, lethargic, stops feeding, poorly controlled body temperature and respiratory rates, may experience seizures, metabolic encephalopathy develops, and can progress to coma and death within the first week of life
Treatment goal = reduce periods of hyperammonemia
*Gene therapy
A
Ornithine transcarbamylase deficiency
17
Q
X linked recessive
Mutation in WAS gene, can also cause X linked thrombocytopenia (XLT), mainly expresses in hematopoietic cells, nucleation promoting factor (NPF) for Arp2/3 complex (binds actin)
Mucrothrombocytes were observed only else in ARPC1B deficiency
Immune deficiency, Thrombocytopenia (low platelet count), Eczema, Recurrent infections, bloody diarrhea,
First signs- petechiae and bruising
Serum IgM low (IgG normal)
Spontaneous nose bleeds and blood diarrhea
Increased risk of leukemia and lymphoma
A
Wiskott Aldrich Syndrome
18
Q
X linked recessive
G6PD deficiency, only enzyme in erythrocytes that supplies NADPH , depletion → oxidation of Hb, RBC turnover, production of bilirubin and jaundice
Yellow skin, dark urine, shortness of breath, fatigue, hemoglobinuria, acte hemolytic anemia, acute kidney failure. Anemia and jaundice in newborns, pale, extreme tired, tachycardia, dyspnea, splenomegaly
Triggers: infection, medication (aspirin or antimalaria quinin), stress of fava beans (favism)
A
G6PD deficiency
19
Q
When homozygotes have more severe phenotypes than heterozygotes or compound heterozygotes, almost all disease with dominant inheritance are in this group
A
incomplete dominance
20
Q
when you have similar phenotype in homozygotes, heterozygotes, and compound heterozygotes
A
pure dominant
21
Q
disease manifests most often when both alleles are mutated (homozygotes or compound heterozygotes), assuming no mosaicism
A
autosomal recessive
22
Q
when a person has 2 or more genetically different sets of cells in his or her body
A
mosaicism
23
Q
if case is not isolated, others affected are usually in same sibship (not observed by parents, offspring, or other relatives) because of low probability, males and females typically equally effected, parents typically asymptomatic, parents may be consanguineous
A
autosomal recessive
24
Q
most molecular basis of recessive disorders involves enzyme deficiencies:
A
inborn errors of metabolism
25
allelic variation may have little to no effect on enzyme activity
polymorphism
26
effects of reduced enzyme activity
1. accumulation of substrate
2. deficiency of product
3. new (toxic) product/alternate pathway
27
AR
VARIABLE EXPRESSIVITY
Genetic and environmental modifiers
Most common fatal AR in white populations
CFTR gene (most common F508 deletion - 70%)
Exocrine pancreatic insufficiency, obstructive azoospermia (no sperm- 95% bc bilateral absence of vas deferens), elevate sweat Cl-, growth failure, meconium elius, idiopathic chronic pancreatitis but some lack clinical signs= partial phenotype
Cystic fibrosis
28
AR
HETEROZYGOUS ADVANTAGE, novel property mutation, compound heterozygosity, ethnic variation
B- globin (HBB) Glu6Val mutation decreases solubility of deoxy Hb → form gelatinous network of stiff fibrous polymers that distort RBC → sickle shape
Sickled erythrocytes occlude capillaries → infarction
Anemia, functional asplenia (inc susceptibility to bacterial infections= major cause of death), failure to thrive, splenomegaly, repeated infections, and dactylitis (painful swelling of hands/feet from occlusion of capillaries, child won’t want to stand),
Newborn screening- initiate antibiotic prophylaxis through age 5
higher level of Hb Fetal associated with lower morbidity and mortality
BCL11A gene- TF that silences gamma-globin expression, silencing can increase HbF (HBG) expression
MYB- TF silences HBG. trisomy 13- high HbF bc miR-15a and miR16-1 target MYB encoded on chromosome 13
Sickle Cell Anemia
29
AR
Mutation in ATP7B gene- 90% (transports excess Cu2+ into bile, excreted in waste products)
Cu2+ metabolism (needed for cytochrome c oxidase/ complex IV and other enzymes) Cu2+ accumulates in liver, brain, and eye
Kayser-Fleischer rings in cornea, low serum caeruplasmin (Cu2+ transport protein), Cu2+ accumulates in liver → hepatitis and cirrhosis and in basal ganglia (brain) → severe progressive neurological disability
Vomiting, weakness, fluid build up in abdomen, swelling of legs, yellow skin, itchiness, tremors, muscle stiffness trouble speaking, personality changes, anxiety, psychosis
Wilson’s Disease
30
AR
Heterozygote advantage (malaria)
Defect/deletion in a-chains of Hb, excess B- chains → nonfunctional B4 tetramers= HbH, precipitate and forms inclusions → removal in spleen and anemia
Infants w/ severe type and high levels of Hb Bart’s (gamma 4) suffer severe intrauterine hypoxia and massive fluid accumulation= hydrops fetalis
Treatment: transfusion (iron overload), bone marrow transplant, gene therapy, hypoxyurea and thalidomide (to induce HbF)
More a-chains lost → inc severity of disease
A-thalassemia
31
AR
Reduces (B+) or absent (B°) synthesis of b-globin chains of Hb tetramer
B chain imp only in postnatal period= later onset
Point mutations (not deletions)
A- thalassemia genes are modifiers for B-thalassemia
Hypochromic, microcytic anemia and an imbalance in globin synthesis due to excess a- chains which precipitate (Heinz bodies)
B-thalassemia
32
AR
Mutation in dynein arms, DNAH5 and DNAl1
80% full term infants present w/ respiratory distress within 24hr of birth, productive “wet” cough begin under 6mo, chronic airway infection, inflammation, progressive obstruction, bronchiectasia (widening of airways), 50% situs inversus totalis (flipped organs), infertility due to sperm and cilial immotility
Kartagener Syndrome
Aka Primary Ciliary Dyskinesia (PCD)
33
AR
Most compound heterozygotes
Mutations in PKHD1, protein polycystin/polyductin (or fibrocystin/polyductin, FPC)
FPC- present in primary cilia of renal tubules and intrahepatic bile ducts
Abdominal discomfort, abdominal mass, polyuria, polydipsia, hypertension with progression to end stage kidney disease by age 15, small # live longer, but have liver dysfn
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
34
AR
Lysosomal storage disease, ethnic variation, genetic drift (Ashkenazi jews), pseudodeficency, population screening
Defect in hexosaminidase (Hex A; GM2→ GM3)
Age at onset: infancy through adulthood
Infants normal til 3-6 mo, then progressive neurological deterioration and loss of motor skills (turning over, sitting, crawling), seizures, vision, and hearing loss, paralysis, cherry red spot on retina (neuronal death), neurodegeneration underlying cause of death at 2-4 yrs
Tay-Sachs Disease
35
AR
Mutation in acid alpha glucosidase (accumulation of glycogen in lysosomes) usually glycogen taken up with autophagy
Progressive muscle weakness (myopathy), born normal, by 3 mo feeding and swallowing problemsn, macroglossia, respiratory difficulties and infections, muscle weakness (floppy baby), hypotonia, hypertrophic cardiomyopathy, die by 2 years
Pompe Disease
Aka glycogen storage disease type II/ floppy baby syndrome
36
AR
Allele heterogeneity
alpha-L-idurondase defect (breaks down unsulfated a-L-iduronic acid found in dermatan sulfate and heparan sulfate- ECM proteoglycans)
Mucopolysaccharidosis type IH (MPSIH) accumulation of glycosamingoglycans (GAGs) in lysosome
Coarsening of facial features, large head with prominent frontal bones, elongates skill, corneal clouding, hearing impairment, hepato- cardio- splenomgaly, umbilical hernia, skeletal abnormalities, lips large, hold jaw open
Life expectancy ~9 yr, bone marrow transplant helps increase survival
Hurler Syndrome
37
AR
Allele heterogeneity
OCA1-deficiency (absence) of enzyme for melanin (tryosinase)
OCA2-defect in the P protein
OCA3- mutation in tyrosinase related proteins
Complete lack or severe reduction of melanin → hypopigmentation of hair, skin, and eyes,
Photosensitivity and reduced visual acuity w/ OCA1- deficiency (most severe)
Oculocutaneous albinism
38
Describes the inheritance where homologous regions at tips of X and Y chromosomes do meiotic recombination which ALLOWS FOR MALE-TO-MALE TRANSMISSION
pseudoautosomal inheritance
39
homologous regions at tips of X and Y chromosomes ____; genetic loci located in these regions are called ____
pseudoautosomal regions
pseduoautosomal loci
40
Dominant
Affects mainly females
SHOX gene mutation
Disproportionate short stature, mesomelic shortening of limbs, bowing of tibia, increased muscle size, deformity of forearms
Leri Weill Dyschondrosteosis
41
male limited precocious puberty meaning only males affected because mutation in luteinizing hormone receptor --> (+) of LHR even without ligand, premature growth spurt, FATHER TO SON TRANSMISSION distinguishes from X linked, mutation in LCGR gene encoding leutenzing hormone receptor
sex-limited AD inheritance
42
Y linked inheritance
(father to son transmission)
Deletion in AZF (azoospermia factor), region of Y chromosome
Mutation in USP9Y
Azoospermina (no mature sperm), oligospermia (low sperm count),
Y chromosome infertility
43
Y linked inheritance
(father to son transmission)
Mutation in SRY (sex determining region Y)
46, XY w/ female external genitalia
No ovaries (“streak gonads”), gonadectomy to prevent gonadoblastoma, hormone replacement therapy to induce menstruation, can become pregnant w/ donated eggs or embryo, no estrogen, breast, or ovaries
Swyer Syndrome
44
transmitted through maternal germline, smaller, circular DNA, homoplasy and heteroplasmy (DNA copies are identical, DNA variant copies), replicative segregation (cell division), disease threshold
Multiple organs affected esp those w/ high energy demands- nerve, muscle, kidneys
Mitochondrial inheritance
45
why does mitochondria need its own translational apparatus?
because genes in mtDNA are using genetic code which is different than that used in nucleus
46
all children of homoplasmic females- WILL inherit mutation
all children on homoplasmic OR heteroplasmic males- WILL NOT inherit mutation
all children of heteroplasmic females- WILL inherit mutation, but not heteroplasmy level
mitochondrial inheritance
47
heteroplasmic deletions not heritable, pleiotropy, variable expressivity, variability in mutation loads btw tissue, father will not have affected children
mitochondrial inheritance
48
Mitochondrial inheritance
Reduced penetrance in females (more males affected
11778 G → A (transition) mutation in MT-ND6 (complex I)
Degeneration of retinal ganglion cells (RGCs) and axons, acute or subacute central vision loss, tobacco and alcohol risk factors, color vision affected visual acuity may improve
Leber’s hereditary optic neuropathy (LHON)
49
Mitochondrial inheritance
3243 A → G (transition) mutation in MT-TL1
Difficulty understanding/thinking, temporary muscle weakness or paralysis (hemiparesis), seizures, hallucinations
Inc in lactic acidosis- vomiting, abdominal pain, fatigue, muscle weakness
Stroke like- weakness/paralysis of an arm or leg or side of body, slurred speech, problems thinking of or saying right word
MELAS
(mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes)
50
not inherited, unstable expansion within affected gene of a segment of DNA consisting of repeating subunits of 3 or more nucleotides in tandem (CAG --> CAGCAGCAGCAG), both germline and tissue specific somatic instability, replication, repair, and recombination contribute to instability,
ANTICIPATION
disease occurs when number of repeats exceeds some threshold (ex Huntington's)
Dynamic mutation
51
disease manifests itself at earlier age as it moves through subsequent family generations --> more severe symptoms
anticipation
52
AD
ANTICIPATION
Parental transmission bias from father (more severe)
CAG (glutamine) repeat expansion in HTT gene (HD gene), stretch of Glu residues sequesters TFs → TFs not available → gene expression affected
Jerky, random, uncontrollable movements=chorea, rigidity, abnormal posture and facial expression, ⅓ psychiatric abnormalities, ⅔ cognitive and motor abnormalities
Huntington Disease
53
how do we get increased number of repeats in Huntington's diseases when transmitted through germline
when CAG repeats gets replicated, the DNA strand may slip back by 3 nucleotides or more and increase number of repeats
54
X linked dominate
Mainly men affected
Somatic mosaicism
ANTICIPATION
Most commonly inherited causing intellectual disability
CGG triplet repeat expansion in 5’ FMR1 gene,
200-1000 repeats= affected , 56-200 repeats= “unstable mutation” (inc risk in next generation)
Promoter silencing by CpG methylation- no FMR1 expression
Post puberty- long face w/ prominent jaw and forehead, large ears, macroorchidism, repeat length mosaicism and methylation determines severity
Fragile X Syndrome
55
AD
1 in 500 Quebec
CTG expansion in 3’ untranslated region of DM1 protein kinase (DMPK1), OR CCTG repeat expansion in intron of CNB gene
DM1 is spliceopathy (abnormal splicing of genes) (CCG serves to bind splicing factors)
Muscle weakness, cataracts, mytonia, “warm up phenomenon”, appears more pronounced after rest and improves w/ muscle activity. Distal muscle weakness, impairment of fine motor tasks, myopathic face or “hatchet face”
Myotonic Muscular Dystrophy
56
AR
GAA expansion in Frataxin (FXN), involved in iron handling and Fe-S cluster biogenesis (esp in mitochondria)
Gene silencing due to abnormal repeats
Difficulty walking and poor balance (ataxia), loss of sensation in arms and legs, impaired speech (dysarthria), scoliosis, primary cause of death= cardiomyopathy
Friedreich Ataxia
57
Centromere in middle, arms same length
metacentric
58
centromere shifted towards telomere
submetacentric
59
chromsomes 13,14,15,21,22, involved in urban translocation, centromere moved to very extreme of one of the arms
acrocentric
60
Most prominent cause of chromosomal abnormality disorders
Nondisjunction
abnormal chromosome segregation
61
when chromosome number does not equal 46
heteroploid
62
chromosomal number = n x 23 (23, 46, 69, 92), covers both normal and abnormal
euploid
63
23 chromosomes (gametes only)
haploid
64
46 chromosomes (normal)
diploid
65
69 chromsomes, can be liveborn
triploid
66
92 chromosomes, fetuses are always spontaneously aborted
tetraploid
67
not euploid, any number of chromosomes, ex) Trisomy 13, 18, 21
ex) XXX syndrome and Klinefelter syndrome (XXY)
aneuploid
68
arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same
nondisjuction
69
arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same
nondisjunction
70
the genome has the normal complement of chromosomal material, 1 in 500, often no phenotype, can interrupt genes reciprocal and non-reciprocal translocation, inversions, or require alternate segregation in meiosis, alternate segregation
balanced rearrangement
71
some material is either added or missing in genome, can be stable or unstable, adjacent segregation, less frequent, partial trisomy (duplication), partial monosomy (deletion, more harmful), marker chromosomes (supernumerary)
unbalanced
72
most common type of translocation, reciprocal, 2 acrocentric chromosomes that fuse near centromere region w/ loss of short arms, often pseudodicentric (centromere inactivated)
chromosomal deletions or addition result in syndromes of multiple malformations, including trisomy 13 (Patau syndrome) and trisomy 21 (Down syndrome).
Robertsonian translocation
73
Can be paracentric (happens in one chromosomal arm) or pericentric (around centromere), fetuses with unbalanced chromosomes from meiosis of paracentric are not viable
inversions
74
What is the similarity and difference between Robertsonian and isochromosomes?
Robertsonian- form of translocation where 2 acrocentric chromosomes fuse at centric ends, forms one large metacentric chromosome and one small fragment, leads to Trisomy 13 and 21
Isochromosomes- made of mirror images of one arms of chromosomes, partial trisomy in isochrome and partial monosomy in lost arm, happens in X chromosome and acrocentric, leads to Turner syndrome
75
range of signs and symptoms that can occur in different people with same genetic condition ex) cystic fibrosis
variable expressivity
76
both alleles of a gene are partially expressed, resulting in an intermediate or different phenotype, most dominant diseases ex) achondroplasia
incomplete dominance
77
similar phenotype in homozygous, heterozygous, and compound heterozygous
pure dominant
78
not all individuals with disease show disease ex) Fabry disease, BRCA 1 do not always show result in breast or ovarian cancer
incomplete penetrance
79
one gene contributes to multiple phenotypic effects ex) untreated PKU manifests with light skin, intellectual disability, musty body odor
pleiotropy
80
if a patient inherits or develops a mutation in a TSG, the wild type allele must be deleted/mutated/eliminated before cancer develop, not true of oncogenes
ex) retinoblastoma and the "2 hit hypothesis"
loss of heterozygosity
81
exerts a dominant effect, a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning ex) osteogenesis imperfecta
dominant negative mutations
82
usually due to defects in structural genes, many generations, both males and females affected, only need one allele to be affected
often pleiotropic (multiple apparently unrelated effects) and variable expressive (different between individuals)
with one affected (heterozygous) parent, each child has 50% chance of being affected
autosomal dominant
83
with 2 carrier (heterozygous) parents, on average: each child has 25% chance of being affected, 50% chance of being carrier, 25% chance of not being affected
usually seen in one generation, more severe than dominant disorders, unaffected individual with affected sibling has 2/3 probability of being a carrier
autosomal recessive
84
sons of heterozygous mothers have 50% chance of being affected. no male to male transmission skips generations, commonly more severe in males, females must be homozygous to be affected
X linked recessive
85
transmitted through both parents, children of affected mothers have 50% chance of affected. 100% of daughters and 0% sons of affected fathers will be affected
X linked dominant
86
variable expression in a population or even within a family due to heteroplasmy
Mitochondrial inheritance
87
both alleles are mutated (a1a2)
compound heterozygosity
88
presence of genetically distinct cell lines in same individual ex) McCune Albright syndrome
mosaicism
89
most cases, only men affected, can skip generations
X linked recessive
90
Families with multiple childhood cancers, specific rare cancers, 2 of more primary cancers
Increased risk of cancers: sarcomas, breast, brain, CNS, adrenal, leukemia
Orphan disease (rare),
No sex predilection, hereditary pattern, cancer incidence varies due to penetrance, cancer present at any age
Li-Fraumeni Syndrome
91
AD
TP53 mutation, p53 protein damaged and unable to function properly
p53= checkpoint proteins in cell cycle, repairs damaged DNA, Tumor suppressor gene
TP53 mutation testing
Sarcoma diagnosed before age 45, first degree relative with any cancer before age 45, first degree or second degree relative with any cancer before age 45 or sacroma at any age
Li-Fraumeni Syndrome
92
Any cancer: weight loss, pain, night sweats; breast cancer: lump, breast changes, breast discharge, CNS cancers: headaches and weakness, leukemia: easy bruising or bleeding, fatigue, recurrent infection
Physical Signs
Any cancer: temporal wasting, cachexia
Breast cancer: palpable mass, peau d’orange, breast changes
CNS: focal neurologic deficits
Leukemia: bruising, pallor,
Genetic counseling, cancer screening, early detection, investigative therapies
Li-Fraumeni Syndrome
93
Risk increases > 45 year old, hereditary syndromes, weight loss, Fe+ deficiency anemia in men, Fe+ deficiency anemia in post-menopausal woman, change in stool caliber or bowel habits, blood in stool
Increases w/ age especially after 45
40 per 100,000 with age over 50, men>women, 20% due to heredity factors, risk factors: red meat and fat consumption, family history, inflammatory bowel disease
Colon Cancer
94
APC inactivation + KRAS activation+ TP53 inactivation
APC= TSG (1st hit) allows for early proliferation
Ras (+) → inc cell cycle → cancer
TP53= TSG
Germline or sporadic APC mutation-
germline= FAP- 100s of polyps, sporadic- most colon cancers
Microsatellite or chromosome instability
Colon Cancer
95
Commonly asymptomatic, weight loss, fatigue and weakness, blood in stool, obstructive symptoms (pain, constipation, stool caliber change), family history of cancer
Pallor, weight loss, fecal blood (occult +, hematochezia) and advanced disease (palpable mass, hepatomegaly, jaundice)
Screening- immunohistochemical testing, colonoscopy, imaging- “apple core” lesion, colonoscopy w/ biopsy
Surgical resection and chemotherapy for localized disease
Chemotherapy and radiation for metastatic disease
colon cancer
96
Weight loss and fatigue, cough, shortness of breath, chest pain, hemoptysis, exposure risk with tobacco use and occupational
Most common cause of cancer death, uncommon below age 40, male > female, 10x increase w/ smoking, occupational exposure
Lung cancer
97
Gain of fn mutations: MYC TFs, RAS (KRAS), RAF (BRAF), FGR1 amplification
Loss of fn mutations: TP53, RB1
Lung cancer
98
Weight loss, anorexia, shortness of breath, cough w/ blood, chest and shoulder pain, tobacco smoke exposure, occupational exposure, paraneoplastic and obstructive symptoms
Tachypnea, hypoxemia, hemoptysis, decreased breath sounds, clubbing, paraneoplastic and obstructive signs
Chest x-ray, CT cancer, bronchoscopy, biopsy
Staging, resection, chemotherapy, radiation, precision therapy to mutation
Lung cancer
99
Asymptomatic, gastroesophageal reflux disease (GERD)- cough, regurgitant symptoms, chest pain, heartburn, hoarseness; dysphagia, obesity and smoking
10-15% of US adults with GERD, 5.6% adults with Barrett’s, 50-60 years old peak age, men> female (3:1)
Barrett’s Esophagus
100
Transient lower esophageal sphincter relaxation (reflux occurs) → GERD → inflammation and cellular stress → intestinal metaplasia → dysplasia → cancer
Esophageal epithelium exposure gastric secretions: bile acids, acidic pH, enzyme exposure (gastric, pancreatic)
Barrett's Esophagus
101
No specific symptoms, look for GERD (heartburn, dyspepsia, chronic cough or hoarseness, brackish taste in mouth, dysphagia, temporal association w/ foods) family history
Elevated BMI, dental erosions, wheezing
Endoscopy, biopsy
Risk factor modification, Proton Pump Inhibitors (PPI), surveillance, endoscopic ablation
Barrett's Esophagus
102
What is the role of cyclins and CDKs in the progression of cell division cycle?
controls the cell-cycle progression via phosphorylation of the target genes, such as tumor suppressor protein retinoblastoma (Rb), leads to progression in S phase
103
What are the 3 fates of cells in the G0 phase?
1) Permanent G0, regenerate from stem cells (neurons, skeletal cardiac muscle, RBCs)
2) G0 stable; can reenter G1 (hepatocytes, lymphocytes, PCT, periostea cells)
3) Never in G0, divide rapidly like cancer cells w/ short G1 (bone marrow, gut epithelium, skin, hair follicles, germ cells)
104
How does the retinoblastoma protein regulate the cell cycle? How is it activated? What is role of the E2F, p21 and p16?
Rb is a TSG that regulates the progression from G1/S phase in the cell cycle. When cell is ready to replicate DNA, Rb activates CDKs which phosphorylates Rb and releases transcription factor E2F. E2F then activates S phase/ DNA synthesis. p21 and p16 are CDKIs that inhibit cyclins
105
What are the CDKs and cyclin pairs in each phase?
cyclin D + CDK 4/6- G1/S phase
cyclin E + CDK2- G1/S phase
cyclin A+ CDK2- S phase
cyclin B+ CDK1- G2 and M phase
106
How is the abundance of CDKIs regulated?
107
What regulates the p53?
phosphorylation by ATM (Ser/Thr kinase) TSG
108
How does the p53 decide on the fate of the cell for cell cycle arrest or apoptosis?
by the extent of DNA damage, if DNA damage is beyond repair (sensed by BAD/BID/BIM) it will undergo apoptosis
109
Which pathway of apoptosis is activated if p53 finds that DNA damage is beyond repair?
Sensed by BAD/BID/BIM, BLC-2 (anti-apoptotic) suppression --> BAX/BAK (OMM channel) induction --> apoptosis (intrinsic, cytochrome c, APAF-1, caspase 9/3, DNase)
110
How do germline mutation, aflatoxin, and HPV alter p53 to cause cancer?
Germline mutation (Li-Fraumeni syndrome) and Aflatoxin inhibits p53. HPV 16 makes E6 which inhibits p53
111
What is Li-Fraumeni syndrome? How does the loss of heterozygosity affect the progression of germline mutation and sporadic mutation of the p53 gene?
Li-Fraumeni syndrome- SBLA (sarcoma, breast, leukemia, and adrenal). Already born with "1st hit" so more susceptible to developing "2nd hit"
112
What is role of p53 in gene transcription? How do the pathways of p53 activation differ under the conditions of DNA damage and oncogene activation?
p53 is a transcription factor that suppresses tumor growth. DNA damage --> cell cycle arrest in G1 for repair. Oncogene will activate p53 (phosphorylated) --> gene transcription
113
How do anticancer drugs relate to the cell cycle? Which drugs are cell cycle non-specific?
Anticancer drugs inhibit the cell cycle. Cell cycle non specific drugs- alkylating agents, antibiotics, nitrosoureas, platinum
114
Why is combination chemotherapy more effective to treat cancer?
targets all dividing cells from all sides, by using different mechanisms of drugs, it decreases the likelihood that resistant cancer cells will develop
115
What are the side effects of MTX and pemetrexed? What is the mechanism of rescue of normal cells by leucovorin?
Side effects- *myelosuppression, *nephrotoxicity, *hepatotoxicity
Rescue for all side effects- LECOVORIN (formyl terrahydrofolate) accumulated more readily by normal cells than by neoplastic cells. Giving this after cancer drug results in rescue of normal cells
116
What is selective toxicity? Why do TMP and pyrimethamine do not cause toxicity in the humans like MTX although all of them inhibit DHFR?
The aim of antimicrobial therapy is to kill or inhibit the infecting organism without damaging the host. They do not inhibit human DHFR
117
What is tumor lysis syndrome? Which drug is used to prevent this side effect of cancer chemotherapy
oncologic emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation; ALLOPURINOL
118
What is the MoA of 5-FU?
metabolites 5-fluorodeoxyuridine monophoase (5-FdUMP, "fraudulent", can't be converted to dTMP) inhibits thymidylate synthetase
119
How do you treat hemorrhagic cystitis caused by cyclophosphamide/ ifosphamide?
N-ACETYLCYSTEINE/ MESNA (Na-2-mercepatoethane sulfonate). they form a non toxic compound with acrolein
fluid intake
120
What are the major side effects of doxorubicin and bleomycin? How do you treat iron-mediated ROS toxicity?
Doxorubicin- myelosuppresion, cardiac damage*, nausea and vomiting
Bleomycin- pulmonary fibrosis
Iron-mediated ROS toxicity: DEXRAZOXANE
121
What do the topoisomerases I & II do to help with the replication and transcription?
Topoisomerase I- breaks and reseals ss-DNA
Topoisomerase II- breaks and reseals ds-DNA
122
How do irinotecan and etoposide work?
Irinotecan---> SN-38 (glucuronidation by UGT1A1 --> bile excretion) (topoisomerase I)
Etoposide- topoisomerase II breaks and reseals ds-DNA
123
What is the MoA of cisplatin?
Platinum compound, intra- and inter- strand linking
124
How do the taxane drugs differ from vinca alkaloids by their action on microtubules?
taxanes bind at a different site than the vinca alkaloids and cause inhibition of mitosis by prevention of degradation of microtubules, rather than prevention of their assembly
125
What are the signs of neuropathy with vincristine?
suppression of deep tendon reflexes early sign, paresthesia hands and toes, cranial nerve damage (hoarseness, facial palsies, or jaw pain)
126
What is reciprocal translocation? How does it generate the Ph chromosome? Which disease is caused by the BCR-ABL fusion protein? What is the mechanism of disease and what is its Rx?
occur when part of one chromosome is exchanged with another; The Philadelphia chromosome is a reciprocal translocation involving chromosomes 9 and 22 that is commonly identified in chronic myelogenous leukemia (CML). The break points of the translocation create a fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22.
Mechanism: inhibition of tyrosine kinase activity
Rx: Imatinib
127
Why can a VEGF blocking drug block tumor growth? What is BEVACIZUMAB?
VEGF receptors that promote angiogenesis; Bevacizumab- recombinant humanized monoclonal antibody against VEGF, Indication- metastatic, age related macular degeneration
128
What is the MoA of rituximab, cetuximab and trastuzumab?
Rituximab- binds to CD20 antigen on > 90% of non-Hodgkin lymphoma cells and on normal B lymphocytes
Cetuzimab- EGFR blocker
Trastuzumab- binds to HER2/neu receptor (RTK of human EGFR2)
129
What are the mechanisms of resistance to chemotherapy?
*increase efflux (p-glycoprotein; MDR), increase metabolism of drugs, increase DNA repair, altered checkpoints (cell cycle and immune), altered molecular targets, decrease apoptosis, decrease influx, vesicular sequestration
130
Why do chemotherapeutic agents cause myelosuppression, alopecia, nausea, vomiting, sterility, and carcinogenicity?
Chemotherapy is killing dividing cells including normal dividing cells like in bone marrow, gut epithelium, skin, hair follicles, germ cells
131
What is the programmed death pathway? How do cancer cells evade immune surveillance?
apoptosis; cancer cells make PD-1 ligands that will keep the normal immune pathway blocked and shut down the immune system
132
What is the MoA of nivolumab, pembrolizumab, and ipilimumab?
Nivolumab and Pembrolizumab- anti-PD-1, binds PD-1 (ligands made by cancer cells, helps keep immune cells from attacking nonharmful cells in the body)
Ipilimumab- anti-CTLA-4, blocks a critical negative regulator of the antitumor T-cell response.
133
from Streptomyces, active in G2 phase. iron catalyzed free radical formation and DNA strand breakage
Hodgkin and Non-Hodgkin lymphoma, testicular cancer. Part of ABVD regimen (Adriamycin) for Hodgkin
pulmonary fibrosis
Bleomycin
134
antibiotics obtained from Streptomyces, idarubicin and mitoxantrone are semisynthetic anthracycline compounds. ROS, Inhibition of Topoisomerase II**, intercalation of DNA, DNA strand break.
breast cancer, bladder and ovarian, Hodgkin disease
myelosuppression, Cardiac damage**, nausea and vomiting. **Rx of ROS-mediated toxicity: Iron chelation w/ Dexrazoxane (binds Fe2+ to prevent ROS toxicity)
Doxorubicin and Daunorubicin
135
inactive until metabolized in liver by CYP450
breast cancer, Hodgkin, non-Hodgkin, leukemia, neuroblastoma, retinoblastoma, osteogenic sarcoma, Wilms tumor
alopecia, bone marrow depression, nausea, vomiting, sterility, **Hemorrhagic cystitis by acrolein (Rx- fluid intake and N-acetylcysteine/MESNA)**
Cyclophosphamide
136
platinum compound, intra and inter-strand linking. During S phase --> unpaired strands --> susceptible alkylation. alkylation of guanine N7 --> base excision --> strand break or pairing of alkylated G with Thymine instead of Cytosine, and substitution of GC by AT. this results in a block at G2 --> **apoptosis **
testicular cancer, other germ tumors, ovarian cancer, bladder, lung, sarcoma, cervical, endometrial, gastric, breast, head and neck cancers
nausea and vomiting, **nephrotoxicity**, toxicity, peripheral neuropathy, hypomagnesemia and K+ wasting
Cisplatin
137
Chronic Myeloid Leukemia (CML): reciprocal translocation t(9;22) (q34;q11) from breakpoint cluster region (BCR) gene on chromosome 22 with tyrosine kinase sequence of Abelson (ABL) gene on chromosome 9 = elongates chromosome 9 and shortened chromosome 22 (Philadephia (Ph) Chromosome) AND = chimeric fusion protein pBCR-ABLE has a constitutive active tyrosine kinase activity
Inhibition of tyrosine kinase activity
CML; gastro-intestinal tumor
Imatinib
138
inhibits tyrosine kinase domian of EGFR
NSCL; pancreatic cancer in combination with GEMCITABINE (2-deoxycytidine analog antimetaboliite that inhibits DNA polymerase
Erlotinib and Geftinib
139
inhibits RTK, including VEGF and PDGF receptors that promote angiogenesis
renal cell carcinoma
Sorafenib and Sunitinib
140
V600 mutation in BRAF gene leads to constitutive activation of B-Raf kinase
melanoma
Dabrafenib
141
--> SN-38 (glucuronidation by UGT1A1 --> bile excretion). synthetic analogs with greater activity and less toxicity TOPOISOMERASE I
Colorectal cancer, lymphomas, breast, cervical, gastric, lung
myelosuppression, diarrhea
Irinotecan
142
renal excretion. synthetic analogs with greater activity and less toxicity TOPOSIOMERASE I
glioma, sarcoma, lung, ovarian tumors
myelosuppression
Topotecan
143
TOPISOMERASE II- breaks and reseals dsDNA
testicular, carcinoma, lung cancer, and non-Hodgkin lymphoma
synergy with platinum compounds (CISPLATIN)
Etoposide (2 sides)
144
recombinant humanized monoclonal antibody against VEGF
metastatic colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, age related macular degeneration
Bevacizumab
145
EGFR blocker. monoclonal antibody immunotherapy
colon cancer
acne like rash
Cetuximab
146
binds to CD50 antigen on > 90% of non-Hodgkin lymphoma cells and on normal B lymphocytes. monoclonal antibody immunotherapy
refractory B-cell Non- Hodgkin lymphoma
Rituximab
147
binds to HER2/ neu receptor (RTK of Human EGFR2). monoclonal antibody immunotherapy ("Trust HER")
metastatic breast cancer (Trastuzumab + Doxorubicin + Paclitaxel). *bystander effect*. Trastuzumab + Emtansine (microtubule disruptor- 34%, Trastuzumab + Deruxtecan (topo I inhibitor- 76%)- linker cleavage by tumor cells release membrane permeable Deruxtecan, this allows low HER2+ neighboring cells to be killed (bystander effect). combination also approved bot HER2+ gastric cancer
Trastuzumab
148
Freezes microtubules in the polymerized state (spindle poison). prevent depolymerization. mitosis inhibition by microtubule stabilization. from Taxus spp. bark tree
NSCLC, ovarian cancer (Carboplatin + Paclitaxel= Rx of choice), metastatic breast cancer. DOCETAXEL for metastatic breast and NSCLC
Neurotoxic, myelosuppression, alopecia
Paclitaxel
149
mitosis inhibition by microtubule disruption. prevent depolymerization
ALL, CLL, non-Hodgkin lymphoma
Neurotoxic peripheral neuropathy (sensory and motor). suppression of deep tendon reflexes early sign. Paraesthesia hands and toes. Cranial nerve damage: hoarseness, facial palsies, or jaw pain. Autonomic neuropathies: orthostatic hypotension, abdominal pain, constipation. No myelosuppression (No L in )
Vincristine (from periwinkle plant)
150
mitosis inhibition by microtubule disruption. prevent depolymerization
ABVD regimen for Hodgkin disease and breast cancer
Myelosuppression (L in Vinblastine; but no neurotoxicity)
Vinblastine (from periwinkle plant)
151
vinblastine derivatives: NSCLC. breast, ovarian
Vinorelbine
152
what is the most efficient bactericidal system in neutrophils
the H2O2 myeloperoxidase (MPO) halide system
153
what comes in after 24 hours of infection, first line of defense
neutrophils
154
what comes in after 48 hours of infection
macrophages
155
what causes defects in leukocyte adhesion, impaired adhesion and migration through endothelium, and presents with lots of infections that cannot heal
Polymorphism Leukocyte Dysfunction Syndrome (genetic)
156
what are the 4 types of acute inflammation cells
serous, fibrinous, purulent (pus), ulcer
157
what are the 5 types of necrosis
coagulative (red and dead)
liquefactive
gangrenous
caseous (cheese-like)
fat (often due to sports trauma)
158
what disease is a genetic deficiency, where engulfment of bacteria does not induce an oxygen-dependent killing mechanism, so the macrophage stays and adds up --> granuloma
Chronic Granulomatous Disease
159
Type I hypersensitivity disease
antigen (smallest)
ex) anaphylactic shock- cannot breathe bc soft tissue in larynx swells
160
Type II hypersensitivity disease
antibodies, directed towards antigen
161
Type III hypersensitivity disease
antibody + antigen
162
Type IV hypersensitivity disease
cells (biggest), mediated by T-lymphocytes
163
ball of macrophages surrounded by lymphocytes
granuloma
164
what is the most common cell stress where tissue decreases in size due to disuse, seen with brain in Alzheimers
atrophy
165
what is abnormal metabolism after cell stress, example is steatosis (fat storage) after drinking alcohol
intracellular storage
166
what is an increase in size of cell after cell stress, due to growth factors (myc), example is uterus getting bigger after birth?
hypertrophy
167
what is an increase in number of cells in a tissue, example is in breast during pregnancy; example arteriole due to hypertension
hyperplasia
168
what is a reversible change from one normal tissue to another to better cope with extracellular environment
ex) columnar to squamous transformative zone, survey here for cervical cancer
metaplasia
169
what is it called when a cancer is confined to an epithelium and restricted to growth in BM, pre cancer, irreversible
dysplasia
leads to neoplasia
170
what is the most common gene mutation in colon cancer
APC gene
171
receptors with intrinsic tyrosine kinase activity that activate transcription factors through these growth promoting genes (3)
MYC, FOS, JUN
172
growth promoting genes that regulate the cell cycle, defects produce oncogenes which lead to uncontrollable cells growth
ex) MYC, FOS, JUN, Ras, ERB2
proto-oncogenes
173
growth inhibiting genes, regulate cell cycle, recessive oncogenes (2 hits)
ex) Rb, p53
tumor suppressor genes (TSG)
174
genes involved in apoptosis, inactivation of these leads to uncontrollable cell growth
BCL-2, p53
175
which apoptosis determining gene is the only one found in mitochondria
BCL-2
176
___ binds to CDK4 and hypo/hyper phosphorylates Rb forming ON/OFF switch
cyclin D
177
How does HPV cause cervical cancer?
HPV makes E6 and E7
E6 inhibits p53 (inhibits response to cell stress)
E7 inhibits Rb (inhibits protein that prevents cell division)
178
Cell death that is IRREVERSIBLE with membrane/organelle rupturing, pathologic, and cell size enlarged
necrosis
179
cell death that is physiologic, involves Bcl2 p53 upregulates Bax, Bad, Bak, cell size is reduces
apoptosis
180
name the cells that come in during tissue repair and time stamp (4)
neutrophils (24 hours)
macrophages (48 hours)
granulation (7 days)
fibrosis/ scar (weeks)
181
what is it called when you have Ca2+ in blood vessel and makes the heart bigger and will kill you
Calcific aortic valvular stenosis
182
What is the MoA for the antibiotic Azithromycin
binds to 50S and blocks peptidyl transferase AND amino acid translocation
183
What is the MoA of Puromycin
aminoacyl tRNA analog, binds A site and acts as a peptidyl acceptor, ABORTING ELONGATION
184
Describe competitive inhibition and an example
Vmax= same, Km= increase (right), binds to same site as enzyme
ex) Provostatin- has similar structure to HMG-CoA in the HMG-CoA reductase active site in cholesterol synthesis
185
Describe noncompetitive inhibition and an example
Vmax= decrease, Km= same; different binding site reduces amount of enzyme active
ex) Lead- inhibits Heme synthesis leading to anemia
186
Describe uncompetitive inhibition and an example
Vmax= decrease, Km= decrease; bind only to formed ES complex (rare)
ex) mycophenolate- inhibits IMP dehydrogenase for nucleotide synthesis and prevents transplant rejection by inhibiting B and T cells (sugar and synthesize base)
187
Describe irreversible inhibition and an example
Vmax= decrease, Km= same; reacts covalently with amino acid residue
ex) Organophosphorous insecticides and nerve gasses- inhibits acetylcholinesterase --> inactivates AcH
muscarinic cholinergic receptors (SLUDGE)- treat w/ Atropine
nicotinic cholinergic receptors (diaphragm paralysis)- intubate
188
mending NON BULKY DNA lesions like alkylated and oxidized base pairs
8-oxo-G binds A instead of C
non bulky DNA ex) AP site
excision of base by GLYCOSYLASE
MUTYH associated polyps (MAP)
NTHL1 associated polyps (NAP)
base excision repair (BER)
189
microsatellite instability ex) telomeres
recognition by MSH6 and MSH2, PMS2 and MLH1 bind, removal w/ Exo 1 (5' --> 3'), resynthesis and ligation
Lynch Syndrome (HNPCC)- mutation in MSH2, MLH1, increased lifetime risk of colon cancer
mismatch repair (MMR)
190
bulky adduct detection
generated by UV light, cisplatin, cigarette smoke, or Aflatoxin
Xeroderma Pigmentosum, Cockayne Syndrome, Combined XP-CS, COPS syndrome, XFE progeroid syndrome
removal of the damaged bases occurs on only one strand of DNA
nucleotide excision repair (NER)
191
happens in G1 when no sister chromatid is needed and ends protected from resection before joining, no homology required, more error prone
non homologous end joining
192
less error-prone, no loss of nucleotides
BRCA 1/2 interacts with RAD51 mutation
5' --> 3' resection, holiday junction
homologous recombination
