Molecular Flashcards
1
Q
Nucleotides: Position of phosphodiester bond.
A
Links a 5’ triphosphate with a 3’ hydroxyl group.
2
Q
Direction of polymerization of nucleic acids.
A
5’ to 3’.
3
Q
Nucleotides:
A. Which are purines? Pyrimidines?
B. Which have one ring? Two rings?
A
Purines are adenine and guanine (2 rings); pyrimidines are cytosine and thymine (1 ring).
4
Q
Nucleotides: Numbers of hydrogen bonds in pairings.
A
Cytosine-guanine: 3 bonds.
Adenine-thymine: 2 bonds.
5
Q
How hydrogen-bonding between nucleotides affects the melting temperature of DNA.
A
Segments of DNA that are rich in C-G pairs melt at a higher temperature than those with mostly A-G.
6
Q
Dimensions of a typical molecule of DNA:
A. Diameter.
B. Length of turn.
C. Number of nucleotides per turn.
A
A. 2 nm.
B. 3.4 nm.
C. 10.
7
Q
Micro-RNAs.
A
Short segments of RNA that regulate levels of messenger RNA.
8
Q
Heterogenous nuclear RNAs (hnRNAs).
A
Include micro-RNAs and messenger RNAs.
9
Q
Structural difference between
A. Adenine and guanine.
B. Cytosine and thymine.
C. Thymine and uracil.
A
A. Adenine has no carbonyl group.
B. Thymine has two carbonyl groups.
C. Thymine has an extra methyl group.
10
Q
RNA polymerases: Direction of action.
A
5’ to 3’.
11
Q
RNA polymerases: Products.
A
RNA polymerase I: Ribosomal RNA.
RNA polymerase II: Messenger RNA.
RNA polymerase III: Transfer RNA.
12
Q
Nucleases:
A. Function.
B. Types.
A
A. To cleave phosphodiester bonds.
B. Exonucleases require a free end; endonucleases do not.
13
Q
Mitochondrial genome:
A. Number of copies per mitochondrion.
B. Number of genes.
C. Products of genes.
A
A. One or more.
B. 37.
C. Oxidative proteins, tRNAs, rRNAs.
14
Q
Heteroplasmy: Definition.
A
Heterogeneity of mitochondrial genomes within one cell (antonym: homoplasmy).
15
Q
Epigenetic regulation: Types (2).
A
Methylation.
Acetylation.
16
Q
CpG islands:
A. Definition.
B. Significance.
A
A. Regions of cytosine-phosphate-guanine sequences.
B. Methylation of the cytosine molecules turns off transcription of adjacent genes.
17
Q
Effect of acetylation on DNA transcription.
A
Acetylation of histones increases transcription of DNA; deacetylation decreases it.
18
Q
Splicing of mRNA:
A. Mediators.
B. Causes of alternative splicing.
A
A. Small nuclear ribonucleoproteins (snRNP).
B. Mutation in site of splice acceptor, splice donor, or branching.
19
Q
Protein structure:
A. Primary.
B. Secondary.
C. Tertiary.
D. Quaternary.
A
A. The sequence of amino acids.
B. The coiling of the polypeptide (e.g. α helix).
C. The 3-dimensional structure of a polypeptide.
D. The combining of polypeptides to make a protein.
20
Q
DNA replication:
A. Stage of cell cycle.
B. Place in the DNA molecule where it begins.
A
A. S phase.
B. At AT-rich “origins”.
21
Q
DNA polymerase: Direction of action.
A
5’ to 3’.
22
Q
Parts of the cell cycle.
A
G1 phase: Diploid.
S phase: Duplication of chromosomes.
G2 phase: Tetraploid.
M phase: Mitosis.
23
Q
Phase of mitosis in which
A. The centrioles move to opposite poles of the cell.
B. The nuclear envelope disappears.
C. The chromosomes are aligned in the middle of the cell.
A
A. Prophase.
B. Metaphase.
C. Metaphase.
24
Q
Period of meiosis in which
A. Recombination occurs.
B. Nondisjunction occurs.
A
A. Prophase I.
B. Meiosis I (mostly) or meiosis II.
25
Periods of meiosis in which the oocyte pauses, and how long these pauses last.
Dictyotene stage (after prophase I): Until puberty.
Metaphase II: Until fertilization.
26
Definition of polymorphism.
A genetic change that causes no harm and occurs in at least 1% of the population.
27
Point mutation: Types (5) and their consequences.
Nonsense: Termination codon.
Missense: Different amino acid.
Silent: Same amino acid.
Splice mutation: Different donor or acceptor site.
Frameshift: Different reading frame.
28
Histones: Charge.
Positive.
29
Nucleosome: Structure.
A sequence of 146 base pairs of DNA wrapped around an octamer of histone proteins (two each of H2A, H2B, H3, H4).
30
Nucleosome: What connects one to the next.
20-50 bases and a linking histone, H1.
31
Packing of DNA into chromosomes.
The chain of nucleosomes is coiled into the 30-nm chromatin fiber, which then forms loops; the loops are formed into minibands, the minibands into chromosomes.
32
Shortest chromosome.
21 (not 22).
33
Classification of chromosomes by location of centromere.
Metacentric: p ≈ q.
Submetacentric: p < q.
Acrocentric: p ≈ 0 and is frequently involved in translocation.
34
Meaning of "22q12.3".
Chromosome 22, long arm, region 1 (nearest to the centromere), band 2, subband 3.
35
Techniques of staining of chromosomes for karyotypes.
G (Giemsa) banding.
Q (quinacrine) banding.
R (reverse-Giemsa) banding.
36
G banding: Areas that take up the stain.
AT-rich areas > GC-rich areas.
37
How to assess the purity of extracted DNA.
Calculate the ratio of absorbance at 260 nm (DNA) to that at 280 nm (protein).
A value <1.8 corresponds with relative purity.
38
PCR: Components (6).
```
Heat-stable polymerase.
Template DNA.
Primers.
Deoxynucleotides.
Divalent cation.
pH buffer.
```
39
PCR: Steps.
Denaturation of DNA at 95 degrees.
Annealing at about 65 degrees.
Extension (polymerization) at 72 degrees.
Return to 95 degrees.
40
PCR: Formula for estimating the number of copies at a particular cycle.
Number of copies = 2^n.
41
Methylation-specific PCR: Purpose.
To detect methylated sequences for amplification.
42
Methylation-specific PCR: Procedure.
Sodium metabisulfate converts methylated cytosine bases to uracil.
Uracil-specific PCR primers are used to amplify the methylated sequence.
43
Reverse-transcription PCR: Purpose.
To detect specific sequences of RNA.
44
Reverse-transcriptase PCR: Procedure.
Reverse transcriptase is used to make a cDNA copy of the RNA; the DNA can then be amplified by PCR.
45
Real-time PCR.
Use of a fluorescent dye to measure the quantity of DNA as it forms.
46
Melting point of DNA: How to measure it.
Incorporate non-hydrolyzable probes or dyes into the DNA.
Measure the fluorescence while incrementally increasing the temperature.
47
Melting point of DNA: Definition (2).
The point at which half the DNA is single stranded.
The point of maximal change in the rate of melting (on a plot of fluorescence vs. temperature).
48
Multiplex PCR: Purpose.
To permit simultaneous identification of multiple PCR products.
49
Multiplex PCR:
A. Procedure.
B. Limitation.
A. Many templates and primers are added to one tube and allowed to react at the same time.
B. Reactions may be affected by competition for limited resources within the system.
50
Transcription-mediated amplification:
A. Purpose.
B. Application.
A. Isothermal amplification of RNA.
B. Mainly in the study of infectious agents.
51
Types of blotting (3).
Southern: DNA.
Northern: RNA.
Western: Protein.
52
Sanger sequencing: Principle.
Incorporation of dideoxy-bases to cause termination of strand elongation.
The different strands can be analyzed by electrophoresis.
53
Sanger sequencing: Modern adaptation.
The dideoxy-bases are labeled with different fluorochromes and incorporated in one reaction. The products are analyzed by capillary electrophoresis and detection of fluorescence.
54
Pyrosequencing: Principle.
A molecule of pyrophosphate is released upon the formation of a phosphodiester bond. The amount of pyrophosphate can be used to determine the sequence of DNA.
55
Chromosome-enumeration probes: Target.
Conserved, highly repetitive sequences of satellite DNA, often near the centromeres.
56
Locus-specific probes: Types (2).
Fusion probes: Used for well-defined translocations with conserved breakpoints or fusion points.
Breakapart probes: Used when a gene may have various translocation partners.
57
Comparative genomic hybridization: Procedure.
Various probes are applied in metaphase in order to count copies of chromosomes or regions thereof.
58
Comparative genomic hybridization:
A. Application.
B. Limitation.
A. To characterize inherited and acquired (neoplastic) chromosomal abnormalities.
B. Cannot detect unbalanced translocations.
59
Array comparative genomic hybridization:
A. Advantage over conventional CGH.
B. Application.
A. Array CGH has higher resolution.
B. Investigation of a developmentally delayed child with an apparently normal karyotype.
60
Short tandem repeats:
A. Definition.
B. Applications (3).
A. Normally occurring sequences of 2-5 repeated oligonucleotides.
B. Determination of parentage, identification of remains, assessment of chimerism in transplant recipients.
61
Short tandem repeats: Disorders (2).
Unstably inherited: Trinucleotide repeats.
Unstable within an individual: Disorders of mismatch repair.
62
Single-nucleotide polymorphisms:
A. Definition.
B. Frequency in genome.
C. SNP haplotype.
A. Polymorphism of single base-pairs.
B. 1 in 1000 bases.
C. Total of an individual's polymorphisms.
63
Single-nucleotide polymorphisms: Applications (3).
DNA fingerprinting for forensics.
Forming a genetic family tree.
Determining predisposition to diseases, responses to medications, and other traits.
64
Sequencing of whole genomes:
A. Methods (2).
B. Variation.
A. Next-generation sequencing, high-throughput sequencing.
B. Sequencing of whole exomes (exons).
65
Cytochrome P450: Nomenclature.
Example: CYP2D6*1.
```
Superfamily: CYP.
Family: 2.
Subfamily: D.
Isoenzyme: 6.
Allele: 1.
```
66
Drugs whose metabolism is affected by:
A. CYP2D6 (2).
B. CYP2C9 (4).
A. Codeine, tricyclic antidepressants.
B. Warfarin, phenytoin, omeprazole, diazepam.
67
VKORC1.
Vitamin K epoxide reductase: Involved in the metabolism of vitamin K and inhibited by warfarin.
68
Enzymes in which polymorphisms can alter the effect of isoniazid.
N-acetyltransferase.
69
Some genetic disorders are not inherited: How so?
Some are acquired during gametogenesis or early in embryogenesis (germline).
Some are acquired in differentiated cells (somatic).
70
Autosomal-dominant inheritance:
A. Appearance of pedigree.
B. Probability of transmitting the trait.
A. Disease is present in every generation.
B. 50% for each offspring.
71
Autosomal-dominant inheritance: Typical products of affected genes.
Structural proteins, receptor proteins, transmembrane channels.
72
Autosomal-recessive disorders:
A. Appearance of pedigree.
B. Probability of transmitting the trait.
A. Disease may skip generations.
B. 25% per offspring (if both parents are carriers).
73
Autosomal-recessive disorders: Typical product of affected genes.
Enzymes.
74
For which type of Mendelian inheritance are penetrance and expressivity most relevant?
Autosomal-dominant inheritance.
75
How X-linked-recessive disorders may be expressed in females (3).
Homozygosity.
Asymmetric lyonization.
Turner's syndrome.
76
Types of inherited nephritic syndrome (3).
Mild: Benign familial hematuria, thin-basement-membrane disease.
Severe: Alport's syndrome.
77
Penetrance vs. expressivity:
Penetrance: How many who have the mutation express the disease.
Expressivity: Degree to which they express it.
78
Alport's syndrome:
A. Clinical triad.
B. Course.
A. Glomerulonephritis, sensorineural hearing loss, ocular lesions.
B. Hematuria initially; progression to end-stage renal disease.
79
Alport's syndrome:
A. Inheritance.
B. Effect on carriers.
A. X-linked recessive.
B. Asymptomatic hematuria in some.
80
Alport's syndrome:
A. Diagnosis.
B. Appearance on electron microscopy.
A. IHC of biopsy of skin or kidney shows lack of α₅ chain of type IV collagen.
B. Thin or disrupted lamina densa.
81
Congenital nephrotic syndrome: Definition.
Nephrotic syndrome before 3 months of age.
82
Congenital nephrotic syndrome: Differential diagnosis (2).
TORCH infection.
Inherited nephrotic syndrome.
83
Congenital nephrotic syndrome of the Finnish type: Clinical features (3).
Markedly enlarged placenta.
Massive proteinuria in utero.
Nephrotic syndrome by 1 month of age.
84
Congenital nephrotic syndrome of the Finnish type: Electron microscopy.
Abnormal variation in size of slit pores.
Rarefaction of slit diaphragms.
85
Congenital nephrotic syndrome of the Finnish type: Gene, location, and product.
NPHS1 on 19q13.1 encodes nephrin, a key component of the glomerular slit diaphragm.
86
Pierson's syndrome: Clinical associations (2).
Microcoria, death within several months.
87
Pierson's syndrome: Renal biopsy.
Mesangial sclerosis and crescents.
88
Pierson's syndrome: Gene, location, and product.
LAMB2 on 3p21 encodes β₂-laminin, a component of the glomerular basement membrane.
89
Alport's syndrome: Gene and its location.
COL4A5 on Xp22.3.
90
Nail-patella syndrome: Clinical manifestations.
Abnormalities of nails, skeleton, and eyes.
Variable renal disease.
91
Nail-patella syndrome: Renal biopsy.
Basement membrane expanded by fibrillary collagen deposits.
92
Nail-patella syndrome: Inheritance.
Autosomal dominant.
93
Nail-patella syndrome: Gene, location, and product.
LMX1B on 9q34.1 encodes a factor that regulates the transcription of COL4A3.
94
Denys-Drash syndrome: Clinical manifestations (3).
Wilms' tumor, male pseudohermaphroditism, rapidly progressive renal failure.
95
Denys-Drash syndrome: Renal biopsy.
Mesangial sclerosis.
96
Denys-Drash syndrome: Gene and its location.
WT1 on 11p13.
97
Denys-Drash syndrome: Variant.
Frasier's syndrome: Less severe; associated with gonadoblastoma.
98
Familial autosomal-dominant focal-segmental glomerulosclerosis: Clinical presentation.
Onset of the nephrotic syndrome in adolescence or young adulthood.
99
Familial autosomal-dominant focal-segmental glomerulosclerosis: Genes and their products.
ACTN4: α-Actinin.
TRPC6: Transient receptor potential cation channel 6.
100
Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Clinical presentation.
Onset of proteinuria in early childhood.
101
Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Renal biopsy.
Initially resembles minimal-change disease but transforms to FSGS.
102
Familial autosomal-recessive corticosteroid-resistant nephrotic syndrome: Gene and its product.
NPHS2: Podicin.
103
Renal Fanconi's syndrome: Definition.
Proximal-tubular dysfunction with various causes.
104
Renal Fanconi's syndrome: Chemical abnormalities.
Glycosuria, aminoaciduria, phosphaturia, hypokalemia, bicarbonate wasting with subsequent metabolic acidosis.
105
Renal Fanconi's syndrome: Inherited metabolic causes (6).
Cystinosis, tyrosinemia, galactosemia, hereditary fructose intolerance, glycogen-storage diseases, Wilson's disease.
106
Renal Fanconi's syndrome: Acquired causes.
Myeloma kidney, amyloidosis, urate nephropathy, heavy metals, others.
107
Renal Fanconi's syndrome: Other inherited causes (2).
Idiopathic.
Dent's disease: X-linked recessive mutation in CLCN5, which encodes a chloride channel.
108
Autosomal-recessive polycystic-kidney disease: Clinical presentation.
Oligohydramnios with pulmonary hypoplasia.
109
Autosomal-recessive polycystic-kidney disease: Gross pathology.
Kidneys remain reniform but have radially oriented cysts that consist of ectatic, elongated collecting ducts.
110
Autosomal-recessive polycystic-kidney disease: Extrarenal manifestation.
Malformations of biliary plates.
111
Autosomal-recessive polycystic-kidney disease: Gene and its location.
PKHD1 on 6p.
112
Autosomal-dominant polycystic-kidney disease:
A. Incidence.
B. Time of presentation.
C. Penetrance.
A. 1 in 500 live births.
B. Adulthood.
C. 100% by the 5th decade.
113
Autosomal-dominant polycystic-kidney disease:
A. Initial presentation.
B. Gross pathology.
A. Isosthenuria and hypertension.
B. Cortical and medullary cysts.
114
Autosomal-dominant polycystic-kidney disease: Extrarenal manifestations (4).
Cysts in pancreas and liver.
Mitral-valve prolapse.
Intracranial berry aneurysms.
115
Autosomal-dominant polycystic-kidney disease: Gene and its location.
PKD1 on 16p13 in 85% of cases.
116
Cystic renal dysplasia:
A. Inheritance.
B. Gross pathology.
A. Not inherited; may result from ureteral obstruction in utero.
B. Kidneys are not reniform; mixture of cysts and loose mesenchyme; usually unilateral.
117
Cystic renal dysplasia: Associated syndrome.
Meckel-Gruber: Kidney disease, polydactyly, occipital encephalocele.
118
Glomerulocystic kidney disease:
A. Time of presentation.
B. Histology (2).
A. Neonatal period.
B. Dilation of Bowman's capsule; renal dysplasia.
119
Brugada's syndrome:
A. Epidemiology.
B. Typical presentation.
C. Genetic basis.
A. Southeast Asia.
B. Healthy young man dying in his sleep.
C. Mutations in various genes that encode ion-channel proteins.
120
Arrhythmogenic right-ventricular dysplasia:
A. Presentation.
B. Histology.
A. Sudden cardiac death in young adult during physical activity.
B. Fibrous and fatty replacement of myocardium.
121
Arrhythmogenic right-ventricular dysplasia:
A. Genetic defects.
B. Variant.
A. Various.
B. Naxos disease: Heart disease, abnormal skin, woolly hair.
122
Prolonged QT interval: Significance.
Can lead to ventricular arrhythmias.
123
Prolonged QT interval: Inherited syndromes (3).
Romano-Ward (AD, no hearing loss).
Jervell Lange-Nielsen (AR, hearing loss).
Andersen-Tawil.
124
Prolonged QT interval: Metabolic causes.
Hypokalemia.
Hypercalcemia.
Hypomagnesemia.
125
Genes associated with a prolonged QT interval: Most commonly mutated.
LQT1.
126
Which gene is mutated in inherited syndromes of long QT interval in which arrhythmias are induced by ____?
A. sleep
B. auditory or emotional stimulus
A. LQT3.
B. LQT2.
127
Prolonged QT interval: Pharmacological causes (5).
Tricyclic antidepressants.
Phenothiazines.
Macrolides.
Antiarrhythmics, classes IA and III.
128
Andersen-Tawil syndrome:
A. Clinical triad.
B. Gene.
A. Episodic paralysis, long QT interval, dysmorphism.
B. LQT7.
129
Inherited syndromes of long QT interval: Penetrance.
Twice as great in females.
130
Dilated cardiomyopathy: What fraction of cases is genetic?
About one third.
131
Dilated cardiomyopathy, X-linked: Gene.
The gene that encodes dystrophin. Also implicated in Duchenne's muscular dystrophy and Becker's muscular dystrophy.
132
Dilated cardiomyopathy, autosomal dominant: Most common gene.
MYH7, which encodes the β heavy chain of myosin.
133
Hypertrophic cardiomyopathy:
A. Incidence.
B. Gross pathology.
A. Approaches 1 in 500.
B. Thick interventricular septum.
134
Hypertrophic cardiomyopathy: Histology (3).
Hypertrophy of myocytes.
Disarray of myofibers.
Interstitial fibrosis.
135
Hypertrophic cardiomyopathy:
A. Most common mutation.
B. Inheritance.
A. R403Q in MYH7.
136
Familial isolated cardiac amyloidosis:
A. Inheritance.
B. Geographic distribution.
A. Autosomal dominant.
B. High prevalence in Portugal, Sweden, Japan, and parts of Africa.
137
Familial isolated cardiac amyloidosis:
A. Gene.
B. Clinical associations (2).
A. TTR, which encodes transthyretin.
B. Peripheral neuropathy, leptomeningeal amyloidosis.
138
Gene that encodes a very early transcription in cardiogenesis.
NKX2-5.
139
Cardiac defects associated with mutations in GATA-4.
Septal defects (mostly atrial).
140
Holt-Oram syndrome:
A. Cardiac defects.
B. Other clinical feature.
A. Septal defects (atrial or ventricular).
B. Malformations of upper limb(s).
141
Holt-Oram syndrome:
A. Inheritance.
B. Gene.
A. Autosomal dominant.
B. TBX-5.
142
DiGeorge's syndrome: Most common cardiac defects (4).
Tetralogy of Fallot.
Interrupted aortic arch.
Ventricular septal defects.
Truncus arteriosus.
143
DiGeorge's syndrome:
A. Gene implicated in cardiac defects.
B. Type of mutation.
A. TBX-1 on 22q.
B. Microdeletion.
144
Noonan's syndrome:
A. Most common cardiac defects (2).
B. Other clinical features (2).
A. Right-sided defects, esp. pulmonic stenosis; hypertrophic cardiomyopathy.
B. Lymphatic malformations, prolonged coagulation times.
145
Noonan's syndrome: Gene.
PTPN11.
146
Alagille's syndrome:
A. Most common cardiac defect.
B. Gene.
C. Inheritance.
A. Pulmonic stenosis.
B. JAG1.
C. Autosomal dominant.
147
Trisomy 21: Most common cardiac defect.
Malformation of the endocardial cushion leading to ventricular septal defect.
148
Turner's syndrome: Most common cardiac defects (4).
Bicuspid aortic valve.
Coarctation of the aorta.
Dilatation of the aortic root, which predisposes to aortic dissection.
149
Williams' syndrome:
A. Most common cardiac defect.
B. Other clinical manifestations (4).
A. Supravalvular aortic (hourglass) stenosis.
B. Dysmorphic facies, mental retardation, hypercalcemia, defects of connective tissue.
150
Williams' syndrome:
A. Gene responsible for most of the features.
B. Type of mutation.
A. Elastin gene.
B. Microdeletion.
151
Genes associated with a prolonged QT interval: Potassium channels (2).
LQT1, LQT2.
152
True hermaphroditism: Definition.
Presence of both ovarian and testicular tissue, whether separately or together in one organ.
153
True hermaphroditism: Karyotype.
Usually 46,XX, albeit almost always with transposed genetic material that includes the SRY gene.
Sometimes a mosaic of 46,XX and 46,XY.
Never 46,XY.
154
Pseudohermaphroditism:
A. Definition.
B. Leading causes.
A. Discordance between genotypic/gonadal sex and phenotypic (external genital) sex.
B. Males: Androgen insensitivity; females: congenital adrenal hyperplasia.
155
Androgen-insensitivity syndrome:
A. Inheritance.
B. Hormone levels.
A. X-linked.
B. Normal or high testosterone and LH.
156
Kallmann's syndrome:
A. Clinical features.
B. Most common pattern of inheritance.
C. Most commonly affected gene and its location.
A. Hypogonadism due to decreased gonadotropins; anosmia.
B. X-linked.
C. KAL1 on Xp22.3.
157
McCune-Albright syndrome: Classic clinical features (4).
Polyostotic fibrous dysplasia.
Café-au-lait spots.
Precocious puberty.
Other endocrine abnormalities.
158
McCune-Albright syndrome: Reason for variable expression.
All cases are somatic mosaics, the germline mutation being incompatible with life.
159
Familial hypocalciuric hypercalcemia:
A. Inheritance.
B. Chemical findings (2).
A. Autosomal dominant.
B. Hypercalcemia; normal PTH (and normal parathyroid glands).
160
Congenital hypothyroidism: Clinical features.
Normal fetal development due to maternal thyroid hormone.
Postnatal deficiency can impair development of brain.
161
Congenital hypothyroidism: Causes.
Most common: Maternal autoantibodies.
Rare: Genetic; may be related to defects in PAX8 or TSHR.
162
Diabetes mellitus, type 1: Relevance of HLA type.
Relative with for those with HLA-DR3 or -DR4:
2-3 in heterozygotes.
10 in homozygotes.
163
Maturity-onset diabetes of the young:
A. Inheritance.
B. Clinical presentation.
A. Autosomal dominant.
B. Insulin-independent; similar to type 2, but with onset before the age of 25.
164
Hirschsprung's disease:
A. Histology.
B. Associated structural chromosomal abnormality.
A. Absence of ganglion cells; axons are hypertrophic.
B. Trisomy 21 is found in 10% of children with HD.
165
Hirschsprung's disease: Associated syndromes (6).
```
Neurofibromatosis, type 1.
Multiple endocrine neoplasia, type 2a.
Waardenburg's syndrome.
Congenital central hypoventilation.
Familial dysautonomia.
Smith-Lemli-Opitz syndrome.
```
166
Hirschsprung's disease: Related single-gene defects.
RET, GDNF, EDNRB are rarely mutated.
167
Osler-Weber-Rendu syndrome: Relevance of clinical presentation to age.
Children: Epistaxis.
Adolescents: Skin lesions.
Older adults: Gastrointestinal bleeding.
168
Microvillus-inclusion disease:
A. Importance.
B. Inheritance.
A. Leading cause of malabsorption in neonates.
B. Autosomal recessive.
169
Microvillus-inclusion disease:
A. Gross pathology.
B. Histology.
A. Paper-thin wall of small intestine.
B. Villous atrophy; apical intracellular inclusions may be stained with PAS, polyclonal CEA, CD10.
170
Esophageal atresia: Most common association.
Vertebral, anal, cardiac, tracheal, esophageal, renal, and limb syndrome.
171
Esophageal atresia:
A. Clinical presentations.
B. Commonly associated malformation.
A. Polyhydramnios, difficulty in feeding.
B. Distal tracheoesophageal fistula.
172
Pyloric stenosis:
A. Time of presentation.
B. Epidemiology.
A. At 1-6 weeks of age.
B. Males of northern European descent; firstborn.
173
Pyloric stenosis: Associations (4).
Turner's syndrome.
Trisomy 18.
Cornelia de Lange syndrome.
Hirschsprung's disease.
174
Intestinal atresia:
A. Most common anatomic site.
B. Associations.
A. Ileum.
B. Down's syndrome in 30%; most cases are sporadic.
175
Gastroschisis:
A. Definition.
B. Risk factor.
A. Extrusion of intestines through the abdominal wall, without a covering.
B. Young mother.
176
Gastroschisis:
A. Association.
B. Chemical abnormality.
A. Usually isolated.
B. Very high maternal serum AFP.
177
Omphalocele:
A. Definition.
B. Associations (3).
A. Midline extrusion of multiple viscera through abdominal wall, covered by peritoneum and amnion.
B. Cardiac defects, trisomies, Beckwith-Wiedemann syndrome.
178
Celiac disease:
A. Association of disease with HLA alleles.
B. Association of HLA alleles with disease.
A. HLA-DQ2 is present in 95% of patients; most of the rest have HLA-DQ8.
B. Only about 1% of those with HLA-DQ2 or HLA-DQ8 have celiac disease.
179
Biliary fibrocystic diseases:
A. Associations (2).
B. Examples (2).
A. Autosomal-recessive polycystic-kidney disease, nephronophthisis.
B. Congenital hepatic fibrosis, Caroli's disease.
180
Congenital hepatic fibrosis:
A. Histology.
B. Complication.
A. Interstitial fibrosis, enlarged portal tracts, segmentally dilated bile ducts.
B. Portal hypertension.
181
Caroli's disease:
A. Histology.
B. Complications.
A. Segmentally dilated bile ducts.
B. Biliary cholelithiasis, bacterial cholangitis.
182
Alagille's syndrome, biliary manifestations:
A. Clinical presentation.
B. Histology.
A. Cholestasis, often in a neonate.
B. Noninflammatory loss of interlobular bile ducts.
183
Alagille's syndrome: Other clinical features (4).
Facial dysmorphism.
Butterfly-shaped vertebrae.
Posterior embryotoxon.
Congenital heart disease.
184
Hereditary hemochromatosis: Affected organs and tissues (6).
```
Liver.
Pancreas.
Pituitary.
Synovium.
Heart.
Skin.
```
185
Hereditary hemochromatosis: Cause of infertility.
Pituitary disease.
186
Hereditary hemochromatosis:
A. Gene and its location.
B. Most common mutations (2).
C. Most common genotypes.
A. HFE on 6p21.3.
B. C282Y and H63D.
C. C282Y/C282Y and C282Y/H63D.
187
Hereditary hemochromatosis: Penetrance (2).
A. Women are half as likely to develop complications.
B. Most individuals with C282Y/H63D have no disease.
188
Juvenile hemochromatosis: Genes (2).
Juvenile hemochromatosis A: HFE2 (hemojuvelin).
Juvenile hemochromatosis B: HAMP (hepcidin).
189
Other inherited diseases (2) of iron overload and their genes.
Hemochromatosis, type 3: TFR2 (transferrin receptor).
Familial iron overload: FTH1 (heavy chain of ferritin).
190
Wilson's disease: Clinical presentation (3).
Liver disease, neuropsychiatric disease, or hemolysis.
191
Wilson's disease: Liver histology (4).
Inflammation, steatosis, pseudoglycogenated nuclei, increased copper in hepatocytes.
192
Wilson's disease:
A. Helpful tests (2).
B. Unhelpful test.
A. Plasma ceruloplasmin (decreased), urinary copper excretion (increased).
B. Serum copper.
193
Wilson's disease:
A. Inheritance.
B. Gene and its product.
A. Autosomal recessive.
B. ATP7B; ATPase required in the binding of copper by ceruloplasmin.
194
α₁-Antitrypsin deficiency: Gene and its location.
SERPINA1 on 14q31.
195
α₁-Antitrypsin deficiency:
A. Number of alleles.
B. Most common genotypes in the healthy.
C. Most common genotypes in the diseased.
A. About 75.
B. MM >> MS, MZ.
C. ZZ, SZ, SS.
196
α₁-Antitrypsin deficiency:
A. Possible manifestations other than in lung and liver (2).
B. Histology of lung.
A. Panniculitis, vasculitis.
B. Panacinar emphysema with basilar predominance.
197
α₁-Antitrypsin deficiency: Inheritance.
Autosomal recessive.
198
Gilbert's syndrome: Gene, product, and mutation.
UGT1A1; UDP-glucoronosyltransferase; mutation in 5' TATA box of the promoter.
199
Gilbert's syndrome: Incidence.
5% of the population.
200
Crigler-Najjar syndrome:
A. Gene and its product.
B. Types of disease.
A. UGT1A1; UDP-glucoronosyltransferase.
B. In type 1, complete lack of enzyme results in severe neonatal jaundice; in type 2: there is some enzyme, and jaundice appears later.
201
Dubin-Johnson syndrome: Gene.
MRP2 (multidrug-resistance protein 2).
202
Cystic fibrosis:
A. Gene and its location.
B. Most common mutation.
A. CFTR, which encodes a chloride channel; 7q31.2.
B. ΔF508.
203
Cystic fibrosis:
A. Frequency of carriers.
B. Incidence.
In the Caucasian population:
A. 1 in 25.
B. 1 in 2000.
204
Cystic fibrosis:
A. Frequent initial manifestation.
B. Another possible early sign.
A. Meconium ileus.
B. Nasal polyps in children.
205
Cystic fibrosis:
A. Cause of infertility.
B. Cause of liver disease.
C. Causes of bronchiectasis (3).
A. Congenital bilateral absence of vas deferens.
B. Biliary obstruction.
C. Staphylococcus aureus, Burkholderia cepacia, Pseudomonas aeruginosa.
206
Cystic fibrosis: Chemical abnormalities (3).
Hyponatremia.
Hypochloremia.
Metabolic alkalosis.
207
Cystic fibrosis: Possible gastrointestinal manifestations (2).
Chronic diarrhea.
Rectal prolapse.
208
Pearson's syndrome:
A. Clinical dyad.
B. Histology.
A. Pancreatitis and marrow failure.
B. Sideroblastic anemia with vacuoles in precursors.
209
Pearson's syndrome:
A. Inheritance.
B. Mutation.
A. Autosomal dominant.
B. Microdeletion within mitochondrial DNA.
210
Shwachman-Diamond syndrome:
A. Clinical features.
B. Histology.
C. Gene.
A. Marrow failure, exocrine pancreatic insufficiency.
B. Pancreatic fatty change with sparing of islets.
C. SBDS.
211
Johanson-Blizzard syndrome: Clinical features (4).
Pancreatic exocrine deficiency and fatty change.
Hypothyroidism.
Deafness.
Hypoplasia of nasal alae.
212
Alzheimer's disease of early onset:
A. Frequency.
B. Familial cases.
A. 5% of cases of Alzheimer's disease.
B. Half of cases of early onset are familial.
213
Alzheimer's disease of early onset:
A. Mutation.
B. Another clinical situation that may be associated with this mutation.
A. Amplification of APP gene.
B. Alzheimer's disease in trisomy 21.
214
Alzheimer's disease: Gene involved in usual (late-onset) disease.
APOE (apolipoprotein E), particularly the E4 allele.
215
Pick's disease:
A. Synonym.
B. Gene.
A. Frontotemporal dementia with Parkinsonism.
B. MAPT (microtubule-associated protein tau).
216
Parkinson's disease: Genes implicated in familial cases.
PARK1 through PARK13.
217
Dementia with Lewy bodies: Clinical features (4).
Dementia plus at least 2 of the following 3:
Cognitive fluctuation.
Visual hallucinations.
Parkinsonism.
218
Huntington's disease:
A. Gene, location, and mutation.
B. Characteristic feature of inheritance.
A. HTT on 4p; repeat of CAG.
B. Anticipation: Longer trinucleotide repeats, earlier onset, and more severe disease in later generations.
219
Huntington's disease: Relevance to number of repeats to phenotype.
Fewer than 28: Normal.
28-35: Premutation.
35-40: Allele with reduced penetrance.
More than 40: Disease.
220
Huntington's disease: A possible determinant of phenotype other than number of repeats.
Paternal inheritance show strong correlation with early onset.
221
Cerebral autosomal-dominant arteriopathy with subcortical infarctions and leukoencephalopathy: Clinical features.
Migraine headaches, transient ischemic attacks, stroke-like events, progression to dementia.
222
CADASIL:
A. Radiographic features.
B. Histology.
C. Diagnosis.
A. Multiple hyperintense lesions throughout brain.
B. Granular eosinophilic deposits in vascular media.
C. Skin biopsy (vascular changes).
223
Charcot-Marie-Tooth disease:
A. Inheritance.
B. Mutation.
A. Autosomal dominant.
B. Duplication of a 1.5-megabase region of DNA on 17p11.2 that contains the PMP22 gene.
224
Charcot-Marie-Tooth disease:
A. Affected nerves.
B. Histology.
A. Sensory and motor.
B. Prominent "onion bulb" formation.
225
Spinal muscular atrophy:
A. Affected nerves.
B. Most severe type.
A. Lower motor neurons.
B. Type 1 (Werdnig-Hoffmann disease).
226
Spinal muscular atrophy:
A. Inheritance.
B. Gene.
A. Autosomal recessive.
B. SMN1 (survival motor neuron).
227
Dystrophinopathies:
A. Inheritance.
B. Gene, location, mutation.
A. X-linked recessive, with a sporadic mutation in one third of cases.
B. DMD on Xp21.1; mutation in promoter.
228
Duchenne's muscular dystrophy:
A. Time of onset.
B. Histology.
A. Before age 5.
B. Scattered hypereosinophilic small rounded fibers; no dystrophin by IHC.
229
Becker's muscular dystrophy: Clinical features.
Less severe than Duchenne's disease and presents later.
230
Myotonic muscular dystrophy:
A. Inheritance and type of mutation.
B. Manifestations outside skeletal muscle (4).
A. Autosomal dominant; trinucleotide repeat.
B. Dysmotility of smooth muscle; cataracts, abnormalities of cardiac conduction, endocrine disease.
231
Malignant hyperthermia:
A. Presenting clinical feature.
B. Gene.
A. Hypercarbia during anesthesia.
B. RYR1 (ryanodine receptor).
232
Mitochondrial disorders: Common clinical features (5).
Ocular abnormalities.
Skeletal myopathy.
Cardiomyopathy.
Encephalopathy.
Sensorineural deafness.
233
Mitochondrial disorders: Inheritance.
Mitochondrial (maternal) or Mendelian, depending on whether the mitochondrial or nuclear genome is affected.
234
Mitochondrial disorders: Screening tests (4).
Lactic acid in plasma or CSF.
Urinary organic acids.
Ketones.
Acylcarnitines.
235
Mitochondrial disorder: Microscopy (2).
Muscle biopsy . . .
Light: Ragged red fibers on trichrome stain.
Electron: "Parking lot" inclusions.
236
Mitochondrial disorders: Reason for diversity of clinical presentation.
Heteroplasmy.
237
Kearns-Sayre syndrome:
A. Inheritance.
B. Endocrine abnormalities (2).
C. Neurological abnormality.
A. Mitochondrial.
B. Diabetes mellitus, hypoparathyroidism.
C. Cerebellar ataxia.
238
MELAS:
A. Meaning.
B. Clinical presentation.
A. Mitochondrial encephalopathy with lactic acid and stroke-like episodes.
B. Initially normal development; progressive neurological deterioration with stroke-like episodes and seizures.
239
MELAS: Mutation.
Point mutation in mitochondrial gene MT-TL1.
240
Mutation: Cri du chat syndrome.
Microdeletion on 5p15.2.
241
Mutation: Prader-Willi syndrome.
Microdeletion of 15q11.2 on the paternal chromosome.
242
Mutation: Angelman's syndrome.
Microdeletion of 15q11.2 on the maternal chromosome.
243
Smith-Magendis syndrome:
A. Characteristic behavioral abnormalities.
B. Mutation.
A. Self-mutilation, embolokoilomania.
B. Microdeletion on 17p11.2.
244
Mutation: Wolf's syndrome.
Microdeletion on 4p.
245
Miller-Dieker syndrome.
A. Characteristic physical anomalies (3).
B. Mutation.
A. Microcephaly, lissencephaly, vertical furrowing of brow.
B. Microdeletion on 17p13.
246
APC gene:
A. Location.
B. Relevance to colon cancer.
A. 5q.
B. Mutated in 85% of colorectal carcinomas; mutation is an early step in carcinogenesis.
247
APC gene:
A. Most common mutation.
B. Variant.
A. Truncation.
B. Normal APC gene; mutation in gene for β-catenin.
248
Familial adenomatous polyposis:
A. Mutation.
B. Natural history of colon polyps (2).
A. Germline mutation in APC.
B. More than 100 adenomatous polyps by age 35; cancer in most by age 50.
249
Familial adenomatous polyposis: Other neoplasms (5).
Gastric fundic-gland polyps.
Ampullary tumors (adenomas, adenocarcinomas).
Small-bowel adenocarcinomas.
Thyroid cancer.
Fibromatosis.
250
Colon cancers associated with mutated APC:
A. Typical side.
B. Typical histology (4).
A. Left.
B. Origin in a tubular adenoma; pseudostratified nuclei; dirty necrosis; infiltrative advancing edge.
251
Other syndromes associated with germline mutation in APC (3).
Attenuated familial adenomatous polyposis.
Gardner's syndrome.
252
Attenuated familial adenomatous polyposis: Mutation.
Affects the 5' or 3' end of the APC gene.
253
Gardner's syndrome: Clinical features (5).
Typical features of FAP, plus
Epidermal cysts.
Jaw osteomas.
Fibromatoses.
Congenital hypertrophic of the retinal pigmented epithelium.
254
Turcot's syndrome: Clinical features.
Colonic adenomas, tumors of the CNS.
255
Enzymes of mismatch repair:
A. Names.
B. Relevance to colon cancer.
A. MSH2/MSH6, MLH1/PMS2 (dimers).
B. Mutated in 15% of cases.
256
Mutations in enzymes of mismatch repair can lead to mutations in what genes of colon cancer (3)?
BRAF, KRAS, p16INK4a.
257
Microsatellite instability:
A. Definition.
B. Relevance to colon cancer.
A. Alteration in length of microsatellite-repeat sequences.
B. MSI is a surrogate marker for dysfunction of enzymes of mismatch repair.
258
Mutations in genes for enzymes of mismatch repair: Germline vs. sporadic.
Germline: Inactivation of coding sequence.
Sporadic: Hypermethylation of promoter.
259
Germline mutations in genes for enzymes of mismatch repair:
A. Affected genes.
B. Syndrome.
A. MLH1 and MSH2 (90% of cases).
B. Lynch's syndrome (HNPCC).
260
Syndromes arising from a germline mutation in the genes for enzymes of mismatch repair (3).
Lynch's.
Turcot's.
Muir-Torre.
261
Colon cancers arising from dysfunction in genes of mismatch repair:
A. Typical side.
B. Typical histology (6).
A. Right.
B. Origin in sessile serrated polyp; large, exophytic mass; mucinous differentiation; lack of dirty necrosis; lymphocytes infiltrate tumor or form nodules ("Crohn-like" pattern); pushing border.
262
Diagnosis of mismatch repair in a colon cancer: Methods (3).
Immunohistochemistry.
Testing for microsatellite instability.
Full-gene testing.
263
Turcot's syndrome: Gene.
Any that encode enzymes of mismatch repair.
APC is mutated in a syndrome of colon polyps and medulloblastoma that has been incorrectly called Turcot's syndrome [OMIM].
264
Gene mutation(s) to be inferred from IHC that is *negative* for
A. MLH1 and PMS2.
B. PMS2 only.
C. MSH2 and MSH6.
D. MSH6 only.
A. MLH1.
B. PMS2.
C. MSH2.
D. MSH6.
265
Testing for microsatellite instability: Procedure.
DNA from the tumor and DNA from normal tissue or peripheral blood are compared with respect to 5 microsatellites.
266
Mutations that impart resistance to treatment with monoclonal antibodies to EGFR (2).
BRAF: V600E.
KRAS: Mutations in exon 12 or 13.
267
Overexpression of Her2 in gastric and gastroesophageal carcinomas:
A. Frequency.
B. Detection.
A. 20% and 30%, respectively.
B. Either IHC or FISH may be used.
268
Grading of overexpression of Her2 in gastric adenocarcinomas: 0+.
Biopsy: No staining.
Resection: Expression in <10% of tumor cells.
269
Grading of overexpression of Her2 in gastric adenocarcinomas: 1+.
Biopsy: Any cluster of (at least 5) tumor cells with faint staining.
Resection: Faint staining of at least 10% of cells in any part of the membrane.
270
Grading of overexpression of Her2 in gastric adenocarcinomas: 2+ (equivocal).
Biopsy: Any cluster of tumor cells with weak or moderate staining of the basolateral or lateral membrane.
Resection: Weak or moderate staining of at least 10% of cells in the basolateral or lateral membrane.
271
Grading of overexpression of Her2 in gastric adenocarcinomas: 3+.
Biopsy: Any cluster of tumor cells with strong staining of the basolateral or lateral membrane.
Resection: Strong, complete staining of at least 10% of tumor cells in the basolateral or lateral membrane.
272
Juvenile polyposis:
A. Inheritance.
B. Location of polyps.
C. Risk of colon cancer.
A. Autosomal dominant.
B. Large bowel, small bowel, stomach.
C. Moderate.
273
Peutz-Jeghers syndrome:
A. Inheritance.
B. Risk of malignancy.
A. Autosomal dominant.
B. Significantly increased.
274
Peutz-Jeghers syndrome: Classically associated tumors of the reproductive tracts (3).
Ovarian sex-cord tumor with annular tubules.
Cervical minimal-deviation adenocarcinoma.
Testicular calcifying Sertoli-cell tumor.
275
Peutz-Jeghers syndrome: Oropharyngeal manifestations (2).
Mucocutaneous pigmentation.
Nasal polyps in some patients.
276
Testing for microsatellite instability: Interpretation.
At least unstable microsatellites: MSI-high.
One unstable microsatellite: MSI-low.
No unstable microsatellites: Microsatellite-stable.
277
Peutz-Jeghers syndrome: Gene and its location.
STK11/LKB1 on 19p.
278
Gastrointestinal stromal tumors:
A. How many lack a mutation in KIT?
B. Which other genes may be mutated?
A. 5%.
B. Most that lack a mutation in KIT have a mutation in PDGFRA; those that lack both mutations may have a mutation in SDH (succinate dehydrogenase).
279
GIST: Relevance of location of mutation in KIT to response to therapy.
Exon 11: Very likely to respond to imatinib.
Exons 9, 13, 17: About 30-40% likely to respond.
280
Do GISTs without a mutation in KIT respond to imatinib?
Up to 30% of such tumors may respond.
281
Mutation of PDGFRA in GISTs:
A. Most common mutation.
B. Relevance to imatinib.
A. D842V.
B. No response; however, other mutations in PDGFRA may be more responsive.
282
GIST: Associated syndromes (3).
Carney's triad: GIST, pulmonary chondroma, extraadrenal paraganglioma.
Neurofibromatosis, type 1.
Familial GIST syndrome (germline mutation in KIT).
283
Pancreatic ductal adenocarcinoma: Syndromes that impart increased risk (7).
Peutz-Jeghers.
Familial atypical mole-melanoma syndrome.
Hereditary pancreatitis.
Familial adenomatous polyposis.
BRCA2 syndrome.
Ataxia-telangiectasia.
Lynch's syndrome.
284
Amplification of Her2 in breast cancer:
A. Frequency.
B. Histology.
C. Clinical outcome.
D. Treatment.
A. About 20% of breast cancers.
B. High nuclear grade.
C. Poor.
D. Trastuzumab, doxorubicin.
285
Amplification of Her2 in breast cancer: When a cell gets a positive score by IHC.
When there is circumferential staining of the membrane.
286
Use of FISH to test for amplification of Her2 in breast cancer: Procedure.
The number of signals of Her2 is compared with the number of signals of CEP 17 (chromosome 17) and a ratio assigned.
287
Use of FISH to test for amplification of Her2 in breast cancer: Interpretation.
Ratio
>2.2: Positive for amplification.
<1.8: Negative.
1.8-2.2: Equivocal -- count more cells; proceed to IHC is indicated.
288
BRCA genes:
A. Locations.
B. Function.
C. Inheritance.
A. BRCA1: 17q21; BRCA2: 13q12-13.
B. Suppression of tumors.
C. Autosomal dominant.
289
Mutated BRCA gene(s):
A. Lifetime risk of breast cancer.
B. Other organs in which cancer can occur (6).
A. 80%.
B. Ovary, fallopian tube, colon, uterus, pancreas; prostate.
290
Mutated BRCA gene(s):
A. Overall frequency in women with breast cancer.
B. Frequency in Ashkenazi Jewish women.
A. About 5%.
B. About 25%.
291
Mutated BRCA gene(s): Risk of developing cancer in the other breast.
25%.
292
Genes other than BRCA in which mutations confer an increased risk of breast cancer (4).
P53, PTEN, STK11, CDH1.
293
Breast cancer, luminal A:
A. Morphology.
B. ER, PR, Her2.
C. Other IHC staining (2).
A. Low-grade, ductal.
B. ER+, PR±; Her2−.
C. Low Ki-67; CK8/18+.
294
Breast cancer, luminal A:
A. Treatment.
B. Prognosis.
A. Sensitive to endocrine therapy; responds variably to chemotherapy.
B. Overall good.
295
Breast cancer, luminal B:
A. Morphology.
B. ER, PR, Her2.
C. Other IHC staining (2).
A. High-grade, ductal.
B. ER+, PR±, Her2+.
C. Moderate to high Ki-67; CK8/18+.
296
Breast cancer, luminal B:
A. Treatment.
B. Prognosis.
A. Often sensitive to endocrine therapy, variably responsive to chemotherapy.
B. Not as good as that of luminal A.
297
Breast cancer, Her2-positive only:
A. Other IHC staining.
B. Treatment.
A. High Ki-67.
B. Trastuzumab.
298
Breast cancer, basal-like:
A. ER, PR, Her2.
B. Other IHC staining (3).
A. Triple negative.
B. High Ki-67, CK5/6+, p63+.
299
Breast cancer, basal-like:
A. Treatment.
B. Genetic association.
A. Aggressive chemotherapy.
B. BRCA1.
300
von Hippel-Lindau syndrome: Inheritance.
Autosomal dominant.
301
von Hippel-Lindau syndrome: Tumors (7).
Clear-cell renal-cell carcinoma.
Hemangioblastoma of CNS.
Pheochromocytoma.
Pancreatic islet-cell tumor.
Pancreatic cyst.
Cystadenoma of epididymis or of broad ligament.
Papillary tumor of the endolymphatic sac.
302
von Hippel-Lindau syndrome: Gene and its location.
VHL on 3p25-26.
303
Birt-Hogg-Dubé syndrome: Inheritance.
Autosomal dominant.
304
Birt-Hogg-Dubé syndrome: Tumors (5).
Renal-cell carcinoma resembling chromophobe.
Cystic pulmonary lesions with spontaneous PTX.
Fibrofolliculomas, trichodiscomas, acrochordons.
305
Birt-Hogg-Dubé syndrome: Gene, location, product.
BHD (FLCN) on 17p11.2 encodes folliculin.
306
Familial clear-cell renal-cell carcinoma: Mutation.
Germline mutation of 3p.
307
Familial papillary renal-cell carcinoma: Gene, location, type of mutation.
c-MET on 7q31; gain of function.
308
Tuberous sclerosis: Renal tumors.
Angiomyolipoma.
Renal-cell carcinoma.
309
Sporadic clear-cell renal-cell carcinoma:
A. IHC.
B. Genetic abnormalities.
A. Positive: CD10, vimentin, RCC.
B. −3p first; mutations in 14q, 9p, 8p, 6q may follow.
310
Sporadic papillary renal-cell carcinoma:
A. IHC.
B. Genetic abnormalities.
A. Positive: CD10, vimentin, AMACR, CK7.
B. +7, +17, −Y.
311
Sporadic chromophobe renal-cell carcinoma: IHC.
Positive: CD117, CK7.
Negative: Vimentin.
Variable: CD10.
312
Sporadic chromophobe renal-cell carcinoma: Genetic abnormality.
Hypodiploidy.
313
Collecting-duct carcinoma: IHC.
Positive: High-molecular-weight cytokeratin.
Negative: CD10, vimentin.
314
Collecting-duct carcinoma: Genetic abnormality.
−1q.
315
Renal medullary carcinoma: IHC.
Positive: CEA.
Negative: CD10, vimentin.
316
Renal-cell carcinoma with translocation involving Xp11.2: IHC.
Positive: TFE3 (nuclear), CD10.
317
Renal-cell carcinoma with translocation involving Xp11.2: Translocations.
t(X;1).
t(X;17).
318
Renal-cell carcinoma with translocation involving Xp11.2:
A. Histology (3).
B. Behavior.
A. Nested and papillary architecture; clear cells; psammoma bodies.
B. Indolent.
319
Mucinous, tubular, and spindle-cell carcinoma: IHC.
Positive: Vimentin.
Negative: CD10.
320
Mucinous, tubular, and spindle-cell carcinoma: Genetic abnormality.
Loss of 1, 4, 6, 8, 13, 14.
321
Angiomyolipoma: IHC.
Positive: HMB45.
322
Angiomyolipoma: Genetic abnormality.
Loss of heterozygosity for TSC2 on 16p.
323
Wilms' tumor: Genetic abnormality.
Mutation of WT1 on 11p13.
324
Wilms' tumors: Associated syndrome and its genetic abnormality.
WAGR.
Microdeletion involving WT1 and the adjacent PAX6.
325
Synovial sarcoma: Gene.
Expression of TLE1 is correlated with the presence of the translocation but is not entirely specific.
326
Low-grade fibromyxoid sarcoma:
A. Related tumor.
B. Translocation.
A. Hyalinizing spindle-cell tumor with giant rosettes.
B. t(7;16)(q34;p11). Also seen in HSTGR, which is on a continuum with LGFMS.
327
Translocation: Chondroid lipoma.
t(11;16)(q13;p12-13) :: C11orf95-MKL2.
328
Genetic defect: Schwannoma.
−22q12 :: NF2.
329
Most common translocation: Ewing's sarcoma/PNET.
t(11;22)(q24;q12) :: FLI1-EWS.
330
Second most common translocation: Ewing's sarcoma/PNET.
t(21;22)(q22;q12) :: ERG-EWS.
331
Other translocations: Ewing's sarcoma/PNET (3).
t(7;22)(p22;q12) :: ETV1-EWS.
t(17;22)(q21;q12) :: ETV4-EWS.
t(2;22)(q33;q12) :: FEV-EWS.
332
Genetic defects (2): Neuroblastoma.
−1p, +17.
333
Translocations (2): Alveolar rhabdomyosarcoma.
t(2;13)(q35;q14) :: PAX3-FOXO1.
t(1;13)(p36;q14) :: PAX7-FOXO1.
334
Genetic defect: Alveolar soft-part sarcoma.
der(17)t(X;17)(p11;q25) :: TFE3-ASPSCR1.
335
Translocation: Desmoplastic small round-cell tumor.
t(11;22)(p13;q12) :: WT1-EWS.
336
Translocation: Myxoid and round-cell liposarcoma.
t(12;16)(q13;p11) :: DDIT3-TLS.
337
Translocation: Low-grade fibromyxoid sarcoma / hyalinizing spindle-cell tumor with giant rosettes.
t(7;16)(q33;p11) :: CREB3L2-TLS.
338
Translocation: DFSP / giant-cell fibroblastoma.
t(17;22)(q22;q13) :: COL1A1-PDGFB.
339
Translocation: Infantile fibrosarcoma / congenital mesoblastic nephroma.
t(12;15)(p12;q25) :: ETV6-NTRK3.
340
Translocation: Extraskeletal myxoid chondrosarcoma.
t(9;22)(q22;q12) :: NR4A3-EWS.
341
Translocations (2): Angiomatoid fibrous histiocytoma.
t(12;22)(q13;q12) :: ATF1-EWS.
t(2;22)(q33;q12) :: CREB1-EWS.
342
Translocations (2): Clear-cell sarcoma.
t(12;22)(q13;q12) :: ATF1-EWS.
t(2;22)(q33;q12) :: CREB1-EWS.
??????
343
Translocations (2): Synovial sarcoma.
t(X;18)(p11.2;q11.2) :: SSX1-SYT, SSX2-SYT.
???????
344
Translocation (2): Inflammatory myofibroblastic tumor.
t(1;2)(q25;p23) :: TPM3-ALK.
t(2;19)(p23;p13) :: TPM4-ALK.
345
Most common translocation: Lipoma.
t(3;12)(q29;q15) :: LPP-HMGA2.
346
Chromosomal region most often affected in well-differentiated liposarcoma / atypical lipomatous tumor.
12q14-q15.
347
Tumors of the head and neck caused by HPV:
A. Epidemiology.
B. Anatomic location.
C. Clinical course.
A. Young nonsmokers.
B. Oropharynx.
C. Indolent.
348
Tumors of the head and neck caused by HPV:
A. Tumor biology.
B. Testing.
A. Genes E6 and E7 of HPV get incorporated into the cellular genome and suppress p53 and Rb, respectively, with over-expression of p16.
B. IHC for p16.
349
Multiple endocrine neoplasia, type 1:
A. Endocrine tumors (3).
B. Non-endocrine tumors (4).
A. Pituitary adenoma (esp. prolactinoma), parathyroid adenoma, pancreatic islet-cell tumor.
B. Facial angiofibroma, collagenoma, lipoma, meningioma.
350
Multiple endocrine neoplasia, type 1: Genetic abnormality.
Germline mutation of MEN1 at 11q13.
351
Significance of sporadic mutations of MEN1.
Seen in 15-20% of sporadic parathyroid adenomas, islet-cell tumors, and gastrinomas.
352
Multiple endocrine neoplasia, type 2A:
A. Tumors.
B. Genetic abnormality.
A. Parathyroid adenoma, pheochromocytoma, medullary thyroid carcinoma.
B. Mutation in affecting exons 10 and 11 of RET on 10q.
353
Multiple endocrine neoplasia, type 2B:
A. Tumors.
B. Genetic abnormality.
A. Pheochromocytoma, medullary thyroid carcinoma, mucosal neuromas / ganglioneuromas, marfanoid body type.
B. Mutation in affecting exon 16 of RET on 10q.
354
Medullary thyroid carcinoma: Histology in multiple endocrine neoplasia.
Not distinctive, but accompanied by hyperplasia of C cells and by many microscopic foci of medullary carcinoma.
355
Papillary thyroid carcinoma:
A. Mutated genes.
B. Result of these genes.
C. Distribution of these genes.
A. BRAF, RET, RAS.
B. Unregulated stimulation of mitogen-associated protein kinases.
C. Mutually exclusive.
356
Papillary thyroid carcinoma:
A. Most common mutation.
B. Frequency of this mutation in subtypes of PTC.
A. V600E of BRAF.
B. 80% in tall-cell variant, 60% in conventional PTC, 10% in follicular variant.
357
Papillary thyroid carcinoma: Frequency of mutations in RET in sporadic cases.
About 40%.
358
Papillary thyroid carcinoma: Mutation associated with more aggressive behavior.
Mutations in BRAF.
359
Melanoma: Most commonly mutated genes (2) and the clinical significance of each.
C-KIT: 30% of cases; tumors may respond to imatinib.
BRAF: Common in cutaneous melanomas that are not associate with sun-induced damage; may respond to inhibitor of BRAF kinase.
360
Diffuse gliomas:
A. Types.
B. Gene that are mutated early in tumorigenesis.
A. Astrocytoma, oligodendroglioma.
B. IDH1, IDH2.
361
Diffuse gliomas: Differentiating mutations.
Astrocytoma: Mutations in TP53 on 17p13.
Oligodendroglioma: Deletions of 1p, 19q.
362
Diffuse gliomas: Mutation associated with progression to glioblastoma.
Loss of material from 10q.
363
Diffuse gliomas:
A. Mutations associated with higher grade.
B. Amplification of EGFR.
A. Loss of 9p and 10q.
B. Present in higher grades of astrocytoma but not in oligodendroglioma.
364
Nucleotides: Components.
Pentose sugar.
Phosphate group.
Nitrogenous base.
365
Primary glioblastoma: Genetic abnormalities (3).
Amplification of EGFR.
Mutation in PTEN.
Loss of 10q.
No mutation of TP53.
366
MGMT gene and brain cancer:
A. Relation to tumorigenesis.
B. Relation to prognosis.
A. In some glioblastomas, MGMT is silenced through hypermethylation of the promoter.
B. Decreases efficacy of temozolomide and radiotherapy.
367
Oligodendroglioma vs. astrocytoma: Radiology.
Oligodendroglioma: Peripheral, well-circumscribed.
Astrocytoma: Central, infiltrative.
368
Oligodendroglioma vs. astrocytoma: Histology.
Oligodendroglioma: Round, regular nuclei; few glial processes; perineural satellitosis; microcysts filled with mucin.
Astrocytoma: Elongated, irregular nuclei; abundant glial processes.
369
Oligodendroglioma vs. astrocytoma: Immunohistochemistry.
Astrocytoma is more likely to have strong expression of GFAP and p53.
370
Oligodendroglioma vs. astrocytoma: Prognosis.
Oligodendroglioma: Better; loss of 1p and 19q confers a better prognosis.
Astrocytoma: Worse.
371
Oligodendroglioma vs. astrocytoma: WHO types.
Oligodendroglioma: Grade II (oligodendroglioma); grade III (a aplastic oligodendroglioma).
Astrocytoma: Grade II (low-grade); grade III (high-grade); grade IV (glioblastoma).
372
Pilocytic astrocytoma:
A. Genetic abnormality.
B. Frequency of this abnormality.
A. Mutations in BRAF, often with no other genetic abnormality.
B. Found in up to 80% of tumors, but rare in diffuse astrocytoma.
373
Retinoblastoma:
A. Genetic abnormality.
B. Is this abnormality sporadic or germline?
A. Mutation in RB1 on 13q14.
B. 90% are sporadic.
374
Retinoblastoma: Associated tumors (3).
Osteosarcoma.
Tumors of the pineal gland.
Primitive neuroectodermal tumor.
375
Meningioma:
A. Mutation.
B. Gene and its product.
A. −22, particularly affecting 22q12.2.
B. NF2; merlin.
376
Meningioma: Relevance of mutation to subtype (4).
Abnormalities of NF2 are found in
80% of transitional and fibroblastic tumors,
25% of meningothelial types,
virtually no secretory meningiomas.
377
Meningioma: Most common genetic abnormality in tumors of higher grade.
−1p.
378
Medulloblastoma: Syndromes associated with higher risk.
Turcot's, Gorlin's, Li-Fraumeni.
379
Medulloblastoma: Most common genetic abnormalities in sporadic cases (2).
i(17q).
−17p: Associated with more aggressive behavior.
380
Rhabdoid tumor: Genetic abnormality.
Loss of SMARCB1 on 22q11.2, which encodes INI1.
381
Mutations of EGFR in lung adenocarcinoma:
A. Most commonly affected exons.
B. Epidemiology.
A. Exons 18-21, which encode part of the tyrosine-kinase domain.
B. Young Asian female; never-smokers.
382
Mutations of EGFR in lung adenocarcinoma:
A. Therapy.
B. Causes of secondary resistance (2).
A. Tumors respond to inhibitors of the tyrosine kinase of EGFR but not to monoclonal antibodies to EGFR.
B. T790M of EGFR; mutations in other genes such as MET.
383
Which type of lung adenocarcinoma has the highest rate of mutation of KRAS?
Mucinous adenocarcinoma.
384
Mutations of ALK in lung adenocarcinoma: Genetic basis.
Interstitial inversion in 2p leads to EML4-ALK translocation.
385
Mutation of ROS1 in lung adenocarcinoma:
A. Frequency.
B. Therapy.
A. Present in 1-2% of tumors.
B. May respond to tyrosine-kinase inhibitors.
386
Lynch's syndrome:
A. Associated female genitourinary malignancies (2).
B. Risk of each.
Endometrial (esp. lower uterine segment): 50%.
Epithelial ovarian (esp. clear-cell type): 10%.
387
Hereditary breast/ovarian cancer:
A. Genes.
B. Risk of ovarian cancer.
C. Precursor lesion.
A. BRCA1, BRCA2.
B. Tenfold.
C. Serous tubal intraepithelial carcinoma.
388
Factors that determine malignant transformation due to HPV.
Ease of integration of HPV DNA.
Alleles of the viral genes E6 and E7.
389
Tuberous sclerosis: Cutaneous abnormalities (4).
Facial angiofibroma.
Subungual or perungual fibroma.
Hypomelanotic macule.
Connective-tissue nevus.
390
Tuberous sclerosis: Major ocular abnormality.
Retinal hamartoma.
391
Tuberous sclerosis: Major CNS abnormalities (3).
Cerebral cortical tuber.
Subependymal nodule.
Subependymal giant-cell astrocytoma.
392
Tuberous sclerosis: Cardiovascular abnormalities (2).
Cardiac rhabdomyoma.
Lymphangioleiomyomatosis.
393
Tuberous sclerosis: Major renal abnormality.
Angiomyolipoma.
394
Tuberous sclerosis: Oral abnormalities (2).
Dental enamel pits.
Gingival fibromas.
395
Tuberous sclerosis: Associated malignancies.
Renal cancers, esp. clear-cell RCC.
396
Tuberous sclerosis: Inheritance (2).
Autosomal dominant.
60% of mutations arise de novo.
397
Tuberous sclerosis: Genes, locations, products.
TSC1, 9q34, hamartin (80% of cases).
TSC2, 16p13, tuberin (20%).
398
Gorlin's syndrome:
A. Major features (3).
B. Associated malignancies (3).
A. Odontogenic keratocysts, multiple basal-cell carcinomas, bifid ribs.
B. Medulloblastoma, meningioma, rhabdomyosarcoma.
399
Gorlin's syndrome:
A. Inheritance.
B. Gene and its location.
A. Autosomal dominant.
B. PTCH1 on 9q22.3.
400
Neurofibromatosis, type 1:
A. Inheritance (2).
B. Gene, location, product.
A. Autosomal dominant; half of cases are sporadic.
B. NF1, 17q11.2, neurofibromin.
401
Neurofibromatosis, type 1: Cutaneous abnormalities (3).
Café-au-lait macules, neurofibromas, freckling of groin or axilla.
402
Neurofibromatosis, type 1: Ocular abnormality.
Lisch nodules.
403
Neurofibromatosis, type 1: Common bony abnormalities (2).
Dysplasia of wing of sphenoid; vertebral dysplasia.
404
Neurofibromatosis, type 1: Associated malignancies (7).
```
Pheochromocytoma.
Ampullary adenocarcinoma.
Leukemia.
MPNST.
Medulloblastoma.
Optic glioma.
Breast cancer.
```
405
Neurofibromatosis, type 2:
A. Inheritance (2).
B. Gene, location, product.
A. Autosomal dominant; 30% of cases are sporadic.
B. NF2, 22q, merlin.
406
Neurofibromatosis, type 2:
A. Characteristic tumor.
B. Other tumors (3).
A. Schwannoma of both vestibular nerves.
B. Meningiomas, ependymomas, pilocytic astrocytomas.
407
Beckwith-Wiedemann syndrome: Site of genetic abnormality.
11p15.5, where maternally derived alleles are preferentially expressed.
408
Beckwith-Wiedemann syndrome: Fetal abnormalities (4).
Macrosomia, polyhydramnios, large placenta, long umbilical cord.
409
Beckwith-Wiedemann syndrome: Other abnormalities (4).
Hemihypertrophy, macroglossia, omphalocele, anterior creases or pits on ears.
410
Beckwith-Wiedemann syndrome: Associated tumors.
Hepatoblastoma, nephroblastoma (Wilms' tumor).
411
Chromosomal-breakage syndromes:
A. Molecular basis.
B. Examples (5).
A. Defects in mechanisms of DNA repair.
B. Bloom's syndrome, ataxia-telangiectasia, Fanconi's syndrome, Nijmegen syndrome, xeroderma pigmentosa.
412
Cowden's syndrome:
A. Gastrointestinal abnormality.
B. Abnormalities of soft tissue.
A. Hamartomatous intestinal polyps.
B. Multiple lipomas and fibromas.
413
Cowden's syndrome: Mucocutaneous abnormalities (4).
Facial trichilemmomas.
Papillomas.
Palmoplantar keratoses.
Palmoplantar hyperkeratotic pits.
414
Cowden's syndrome: Other abnormalities.
Genitourinary abnormalities.
415
Cowden's syndrome: Abnormalities of the CNS (3).
Microcephaly.
Mental retardation.
Cerebellar dysplastic gangliocytoma (Lhermitte-Duclos lesion).
416
Cowden's syndrome: Tumors (4).
Follicular carcinoma of thyroid gland.
Carcinomas of breast, colon, endometrium.
417
Cowden's syndrome:
A. Gene and its location.
B. Related syndromes (2).
A. PTEN on 10q23.
B. Bannayan-Riley-Ruvalcaba, Proteus.
418
Carney's complex: Cutaneous abnormalities (3).
Nevi.
Lentigines.
Myxomas.
419
Carney's complex: Cardiovascular abnormality.
Cardiac myxoma.
420
Carney's complex: Endocrine tumors (3).
Follicular adenoma of thyroid gland.
Pituitary adenoma.
Primary pigmented nodular adrenocortical disease.
421
Carney's complex:
A. Genitourinary tumor.
B. Other syndrome in which this tumor is seen.
A. Large-cell calcifying Sertoli-cell tumor.
B. Peutz-Jeghers.
422
Carney's complex: Neurological tumor.
Psammomatous melanotic schwannoma.
