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1)  Name the three types of Heterogeneity; give a brief description and example of each. 



2)  Name the three types of Heterogeneity that account for variation in clinical phenotype in several inherited disorders.

I) Types of Heterogeneity:

1.  o Allelic heterogeneity - one gene with more or less severe mutants;  

• Ex: CF (CFTR gene has 1400 diff mutations = CF, different severities)
• Ex: PKU (PAH gene mutations)
•  Also PKU (d/t PAH gene mutations)

2. Locus heterogeneity - same disease, caused by different mutant genes;  

• Ex: Retinitis pigmentosa  (photoreceptor degeneration, manifested by >70 diff mut)
• Ex: Hyperphenylalanemias (PKU is in this category, but is not locus hetero.)

3.  Phenotypic heterogeneity – mutant in 1 gene causes different diseases

• Ex: Hirschsprung Disease (mutation in Ret gene - tyrosine kinase receptor gene)
• 1 mutation = no colonic ganglia dvlpmt →Narrowing of distal colon→ chronic constipation, dominantly inherited
•  cancer of thyroid & adrenal glands (multiple endocrine neoplasia type 2A & 2B) dominantly inherited
•  BOTH Hirschsprung disease & endocrine cancer 


II) Clinical Phenotype Variation:

  • allelic heterogeneity: diff alleles of the same gene cause varying disease severity; example of PAH
  • locus heterogeneity: muts in different genes can yield same disease; for example, phenylalanemia
  • modifier genes: people (even within families) with the same mut can present different phenotypes due to the presence of modifier genes; classic example is ApoE4, if you carry 1 or 2 alleles of ApoE4(worse than other Apo’s) you are more susceptible to a range of neurological and neurodegenerative disorders;   common variants in genes can affect the onset & severity of a disease but don’t cause disease itself; ex.  people with 1 or 2 copies of the E4 allele of ApoE are at a greater risk for Alzheimer Disease (AD) 





What is a "Proband" 

In pedigree analysis, "Proband" refers to a particular subject being studied or reported on. In pedigrees, the proband is noted with an arrow and the box (male) or circle (female) shaded accordingly.


4 Basic Patterns of Inheritance

  1. Autosomal Dominant 
  2. Autosomal Recessive (AR)
  3. X-linked Dominant
  4. X-linked Recessive


Penetrance vs. Expressivity

People w/ same disease-causing genotype have varying phenotypes…  

o Penetrance: probability that a mutant gene will have a phenotypic expression  

• Reduced penetrance: when the expression of a mutant phenotype is less than 100%

o Expressivity: severity of exprsn of the phenotype among individuals with the same genotype

• Variable expressivity: when the severity of the disease differs in people who have the same genotype
• Ex: Neurofibromatosis (NF1) = pleiotropy, wide range of xprsn in tissues (café au lait spots, harmartomas on iris, tumors, neurofibromas on skin) phenotype depends on body location of NF1 mutation
• NF1 can randomly appear, then be passed on thru generations 


Name & Describe 4 ALTERNATIVE Patterns of Inheritance

• Y-linked dominance
o ~20 genes on Y
• SRY genes most important – sex determining
o Inherited Y-linked disorders are rare, but dominant by definition
o Most involve various forms of infertility / reproductive abnormalities
o One form of male deafness is associated w/ Y
o Pedigree – Only affects males, every father to every son

• Mutational Mosaicism
o X-inactivation is one example
o Can occur in either the germline or somatic cells
• can form abnormal tissue/organ
o Seen in childhood cancers & developmental disorders
• Ex: Osteogenesis imperfecta, an AD disease that affects bone development
• both affected children have the same point mutation in a collagen gene
• father is unaffected and has no such mutation in his somatic cells
• mosaic for a new mutation in his germline

• Unstable Repeat Expansion Disorders / Premutation Alleles
o Mutation can change from one generation to the next
• premutation (no phenotype) → mild phenotype → more severe phenotype
o Unstable triplet repeat that can cause CNS diseases (AD, AR, X-linked)
• severity correlates w/ the length of the repeats
• ex: Huntington Disease, Fragile X, Myotonic Dystrophy, Friedrick Ataxia

• Maternal inherited mut Mitoch. genome:
o Segregation of mitochondria during cellular replication is random – some daughter cells can receive more mitoch than others
o Mother → all children!
• Some may not be as severe
o Father → No children


What is a "Haplotype" or "Haplotype Block"?

• haplotypes (short for haploid genotypes):  any combination of alleles, loci, or markers on the same chromosome that are inherited together


  1. o not really mendelian, it’s a subtle susceptibility to a disease
  2. o think of it as a “block” of genes/markers that are usually inherited all on the same chrom
  3. • sets of SNPs (haplotypes) have more statistical power to identify disease genes and regions


Know the in's and out's of Prader-Willi and Angelman Syndrome: 

  1. Presentation
  2. Susceptibility
  3. Allele function
  4. Maternal vs. Paternal imprinting
  5. snRNAs (SNORD 116 & UBE3A)
  6. Mosaicism in imprinting

Prader-Willi and Angelman Syndrome
• Dvlpmntal mental retardation – childhood
• Area of genome with PW/A is a hotspot for deletions/recombo
• Only 1 fxn allele = functional hemizygous
o Anything that leads to loss of fxn of the one allele (loss of chrom, deletion, mut, etc.) will give rise to either PWS or AS
o PWS and AS usually deleted together

P-W = maternally imprinted, if mutation occurs in the expressed allele (from father), no gene product is made, PWS
o Caused by small nucleolar RNA (snoRNA – noncoding), loss of this gives rise to PWS
o Not due to a gene/protein

A = Paternally imprinted, mutation occurs in expressed allele (from mother), results in AS
o Is due to a gene/protein

snRNAs – made w/PWS exprsn, act in silencing UBE3A
Deletion of snRNAs = exprsn of UBE3A
Due to snRNA deletion *snoRNA is a type of snRNA – major causative snRNAs (especially SNORD116)
Imprinting Errors can affect PWS and AS
• Imprinting can go wrong… if imprinting is not erased (to be re-imprinted for gametes) then imprinting could occur on both copies of chroms – equal to a deletion.
• Or, failure to imprint – no imprinting results in more xprsn of a gene (increase in dosage)
• Or, mosaicism in imprinting – imprint gets lost during meiosis
• Can be tied to diseases, cancer
• PWS – see example B
• AS – see example C, D


Describe the "success story" and mechanism associated with BCR-ABL translocation

Cytogenetics in Cancer
• cytogenetic changes common in advanced cancers
• aneuploidy is the most common
• translocations can disrupt tumor suppressor genes or activate oncogenes

BCR-ABL = Philadelphia chromosome in chronic myelogenous leukemia (CML) is a classic example
o 9-22 translocation
o Leads to overxprsn of tyr kinase in hematopoetic cells → leukemia
o Detected by FISH


Down's Syndrome:
  1. What is Down's syndrome?
  2. What are the associated risk factors?
  3. What is the rate among women >45?
  4. What is the risk of recurrence?
  5. What is the likelihood a woman >45 with one Down's child will have another?
  6. What Micro RNA's & genes associated?
  7. What is XIST?

• Trisomy 21, lethal in 75% of fetuses;  most common chrom birth defect: 1/800;  • trisomy 21 usually caused by meiotic non-dysjunction in meiosis I;   disease likely caused by increased gene dosage

• rate inc. to 1/15 in women over 45

• 8-fold (1/100) risk of recurrence

o If a woman 45 or older has one down’s child already, her 1/15 chance (8 fold risk of recurrence) = 50% chance

5 miRNAs on chr. 21 that are overexpressed in DS patients
o two of these, miR-155 and miR-802 were shown to downregulate the expression of a methyl binding protein (MECP2) on a diff chrom
o MECP2 (binds to methyllated cytosines) which causes overxprsn of CREB1 and MEF2C, implicated in the CNS and other phenotypes of DS

XIST:  controls genetic dosing of XXX--> Counts and Silences the extra copy


Describe the tests/results associated with the following Maternal Screening Phases (with particular focus on Down's Syndrome):

  1. Non- Invasive Tests (4) 
  2. Invasive Tests (3)
  3. Prenatal Strategy for DS

1)  Maternal Serum Screening (double, triple, quad)
• first trimester: βHCG (free β-human chorionic gonadotropin) increase in DS; PAPP-A (pregnancy associated plasma protein-A) decrease in DS
• second trimester: can detect alpha-fetoprotein (AFP), unconjugated estriol (uE3), inhibin and human chorionic gonadotropin (HCG)
• depressed levels of AFP (& uE3) and elevated levels of HCG and inhibin A are associated with DS
• increased levels of AFP are associated with neural tube defects such as open spina bifuda
• can have slight overlaps of values in ranges of disease vs normal (ex: AFP) – makes determining risk based on just 1 factor nearly impossible 

2) Ultrasound

3) Radiography

4) MRI



*1-3% risk of miscarriage
chorionic villus sampling: biopsy of tissue from the villous area of the chorion, can occur 4-5 weeks before amniocentesis
amniocentesis: removal of amniotic fluid transabdominally by syringe; fetal cells are cultured for diagnostic tests (FISH – can look for aneuploidy)
cordocentesis: removal of fetal blood from the umbilical cord, more often used when other methods have failed or are ambiguous

• Prenatal Testing Strategy for Down Syndrome

  1. start with non-invasive 1st and 2nd trimester screening in combination; ultrasound plus βHCG and PAPP-A in the 1st trimester, followed by AFP, uE3, inhibin, and HCG in the 2nd trimester; this results in ~95% detection rate for DS
  2. positive non-invasive test results justify confirmative invasive testing, e.g., amniocentesis/FISH
  3. availability of genetic and reproductive counseling



Name some examples of Ecogenetics discussed in class

o Ex: α1-AT polymorphisms, lactase def., ADH def., G6PD deficiency and fava beans 


• ZZ genotype make only 15% of normal AAT protein and are susceptible to diseases
• allele freq vary by ethnicity with Z frequency highest in Caucasians (especially Danes)
• AAT, smoking,  and Survival
• ZZ  non-smokers have much higher survival than ZZ smokers
• AAT variants (Z) also increase risk of liver disease


Heterozygous Advantage:  Sickle Cell Anemia

• β-globin locus (sickle cell anemia)
o thalassemia and sickle cell anemias
o βS allele frequency is 5% in A-A,  higher in some pops in sub-Saharan Africa
o people who are heterozygous for βS allele are resistant to malaria
o βS - deleterious allele maintained in a pop b/c when hetero, inc. reproductive fitness = heterozygous advantage


Allelic vs. Genotypic Frequency

Allele Frequency (gene frequency) = percentage of allele in a population
• problem of defining a population – US genetically mixed!
• determining the allele frequency from a genotype frequency (remember we are diploid organisms)
o just count the alleles:
o Ex: if a population has 20 AA, 10 Aa, and 5 aa –
•  2(20A) + 10A = 50A 
• 2(5a) + 10a = 20a
• 70 total, each are a fraction (50/70 and 20/70)
• NOTE: p+q=1

Genotype Frequency = proportion of indiv in a pop that have a genotype (homo, hetero)
• not as easy since the distribution of alleles between homozygotes and heterozygotes may not be known
Hardy-Weinberg Law - helps determine carrier frequency/gene mapping in pop and mutation rates
             p2 + 2pq + q2    (comes from punnet sq)

Which pop is in HW equilibrium?

o Pop.              AA           Aa              aa
  X                0.25         0.50           0.25 (q = 0.5) – correct
  Y                0.10         0.74           0.16 (q = 0.4) – incorrect for p & 2pq
  Z                0.64         0.27           0.09 (q = 0.3) – incorrect for p & 2pq


List the 9 Cellular/Biochemical Disease Classifications, and give an example for each.

Enzyme Defects
• enzymes contain critical regions that can be disrupted by mutations
o PKU - relatively common defect in newborns that is tested for at birth
o PKU is an example of defect that occurs in one tissue (liver & kidney) but where the phenotype is manifest elsewhere (brain)

Defect in Lysosomal Storage
• increases in tissue mass, common cause of neurodegeneration and other CNS problems
• heterogenous group of ~ 40 genetic disorders, caused by muts in lysosomal enzymes, aut recessive
o  ex: Tay-Sachs disease, a buildup of GM2 ganglioside sphingolipids, mutation in hexA gene
• ubiquitously expressed, mutant phenotype in brain (retina spot with white area around it) 
• Tay-Sachs 100 times more prevalent among Ashkenazi Jews; carry a mutant hexA allele
• homozygous infants are normal until 3-6 months, then neuro problems begin, death between 2-4 years

Defects in Protein Trafficking
• many proteins are post-tln modified (add sugars, signals for trafficking)
• ex: I-cell disease, no M-6-P tag for lysosome enzymes, sent out of cell instead

Defect in Co-Factor Metabolism
• ex: α1-AT, co-factor in interactions with environmental factors like cigarette smoke

Defects in Receptor Proteins
• ex: LDL-R- which is responsible for binding & internalization of LDL & cholesterol
• hypercholesterolemia is an autosomal dominant disorder (hemidominant – heterozygotes also have some symptoms) arising from LDLR defects, and is common familial disease more severe in homozygotes

Defects in Transport
• classic example is cystic fibrosis (CF), an autosomal recessive disease
• CF caused by F508 mut in the CFTR gene - chlorine channel in the apical membrane of epithelial cells

Defects in Structural Proteins
• example: DMD an X-linked recessive disease, mut in the dystrophin gene; causes progressive muscle deterioration from childhood on, leading to death by late teens; currently untreatable but gene therapy trials are underway
o dystrophin has two functions: maintains muscle-membrane integrity, linking actin skeleton to the ECM; and it maintains synaptic junctions in the brain
• 1/3 of DMD arise from new mutations b/c of the size of the gene & because of higher mut rates in sperm
• carrier mothers have no clinical manifestations but often show elevated creatine kinase levels

Neurodegenerative Defects
• Alzheimer’s disease - 1st degree relatives have a 38% risk of AD and 10% of AD is familial (clusters of disease in certain families)
• triplet repeat expansion disorders, including Huntington disease

Mitochondrial Disorders
• mitochondria encode either tRNA or oxidative P proteins
o high mut rate
• mitochondrial diseases found in tissues with high energy demands: CNS and muscle
• maternally inherited, affected males cannot pass on a mitochondrial disorder
• mosaicism


What is genetic mapping?  

Describe Linkage Analysis. 

A way to characterize the genetic basis for a phenotype within a given family.  Does not require knowledge of sequence.

A genetic map indicates the relative position of genes (defined by fxn) shown by linkage analysis

• linkage analysis determines whether two genes/loci/markers, are near one another, estimated by the frequency that they are transmitted together during meiosis
• 2 genetic loci are linked if they are transmitted together more often than expected.  the closer two genes or markers are to each other the less likely they will be separated during meiotic recombo
o Far apart: recombo likelihood = nonrecombo likelihood (50%) unlinked
o Close: nonrecombo likelihood > recombo likelihood (less than 50%) linked


What is Recombination frequency?

How long is 1 centiMorgan, and how is it derived?

If a Genetic Marker is recombined independently from the disease gene (AKA, no longer detected on same chromosome as disease gene) in only 1/25 progeny, how close is the marker to the disease gene? 


Recombination frequency (θ) is the frequency with which a single chromosomal crossover will take place between two genes during meiosis. The recombination frequency will be 50% when two genes are located on different chromosomes or when they are widely separated on the same chromosome. This is a consequence of the law of independent assortment.  The law of independent assortment always holds true for genes that are located on different chromosomes, but for genes that are on the same chromosome, it does not always hold true.  When two genes are close together on the same chromosome, they do not assort independently and are said to be linked. Whereas genes located on different chromosomes assort independently and have a recombination frequency of 50%, linked genes have a recombination frequency that is less than 50%.

A centiMorgan corresponds to appx 2MB of genetic sequence separation.  It is quantified by 1% of observd Recombination Frequency between two genes on a chromosome.  

1/25 = 4% = 4cM.  This independent recombination event is rare, because the marker and gene are located very close together on the same chromosome. 



Compare Linkage Equilibrium and Disequilibrium

Linkage Equilibrium = freq of the marker alleles and the disease alleles correspond,

o For example, if a marker locus (A, a) has allele frequencies of A = 0.7, a = 0.3, then disease gene linked to “A” in 70% of affected families and to “a” in 30% of affected families.

Linkage Disequilibrium =  Frequencies vary

Indicates that the allele marker is very close to the disease gene (how the CF gene was cloned)
o Linkage Disequil is when 2 genetic loci, across the pop as a whole, are found together more often than expected, non-random association
• haplotypes (such as SNP haplotypes) can be in equilibrium or disequilibrium. 


How might you map a single-gene (monogenetic) trait?

Give an example of a monogenetic trait and how it was initially mapped. 

Mapping Primarily Single-Gene Trait Genes

• Easier to map than complex diseases – linkage analysis
• special considerations: reduced penetrance and variable expressivity
• polymorphic markers can be used in families, including linkage analysis of SNPs and SNP haplotypes

• Ex: SNP haplotypes to map a monogenic disease gene
o Ehlers-Danlos VIII disease is a rare aut dominant disorder involving a collagen defect
o initially mapped to chr. 12 in families (used LOD), one large fam permitted mapping of SNP haplotypes
o causative gene has not been identified yet


o Ex:linkage analysis for primarily single-gene diseases in families
• enroll families: either very large families (e.g., Nancy Wexler with Huntington's Disease) or many small families (e.g., CF)


How might you map a complex-trait disease gene?

Give an example of two methods.

Mapping Complex Trait Disease Genes

 association analysis OR  sib-pair analysis 

Association Analysis:

Mapping of (CAPN10) : a type-2 diabetes gene (T2D) in Mexican American Families

• sequenced all of the genes & found 5 SNPs in the CAPN10 gene that were in linkage disequilibrium with a risk for T2D
o 4 SNPs were in introns and one in exon 10, introns strongest link
• SNPs in CAPN10 accounted for ~ 20% of the risk for T2D in Mexican Americans; studies repeated in ~ 20 other other populations confirmed the association
• SNPs interfere w/insulin secretion and glucose uptake

Type-2 diabetes in Oji-Cree of Sandy Lake
• T2D in the Oji-Cree is the third highest in the world; ~40% of this population develop T2D
• association analysis identified a coding SNP that resulted in a G319S mutation in the HNF-1α gene
• One mutant allele have 5 times greater risk of T2D, Two mutant alleles have 25 times greater risk


uses small families, asks whether affected siblings share specific alleles at a freq higher than expected
• sibs get same allele from same parent = identical by descent (IBD) --> MOST IMPORTANT!!!
(always identical by state as well)
• sibs get same allele from diff parents = identical by state (IBS)
Use of Sib-Pair Analysis
• need to know whether alleles are IBD or IBS
• if a locus is linked to a disease gene, the # of alleles that the sibs share will be somewhat greater than 1

Example of Sib-Pair: Hirschsprung Disease
• Most common form of inherited intestinal obstruction; wide variation in phenotype, complex inheritance
• study examined 67 sib-pairs that are concordant for Hirschprung disease and they found that 55/67 shared three polymorphic markers, while the other 12 shared at least two of three polymorphic markers
• follow up analysis identified defective genes at each of these loci, particularly the RET gene


Pair the following cancers with their tissue of origin:

• Carcinoma
• Sarcoma 
• Hematopoietic/Lymphoid 

• Carcinoma = epithelial
• Sarcoma = connec tissue
• Hematopoietic/Lymphoid = leukemias & lymphomas


Describe the Cancer Stem Cell Hypothesis

• CSC hypothesis proposes that many cancers are driven by tiny subpops of unique CSCs
• different types of cells in tumors: some cancerous, some stromal, some different phenotypes
• if every cancer cell has the potential to form a tumor (clonal evol hypothesis), then few cells should be required to form a tumor, thus tumors contain a cell hierarchy in which only a few SC’s can self-renew
• it is possible that survival is a quality of a stem cell
• cancers are hierarchically arranged with CSCs at the apex, CSC are the only cells that can self-renew
Clinical Implications of CSC Hypothesis
• cytotoxic agents are designed to kill proliferating cells but are not curative because CSCs remain
o the great bulk of tumors arise from differentiation and cannot make a tumor on their own
• normal SCs have multidrug & apoptotic resistance, quiescent CSCs are also thought to be resistant
o differ from normal SCs by their impairment in differentiation
• effective strategies: induction of differentiation of CSCs, perhaps epigenetically




Inherited: 1 mut* (fxn hemizygous) - only need 1 more mut = cancer
Sporadic:  need 2 muts* on same allele on 2 chroms = cancer, much longer/less likely

*Muts can be:
Dominant - gain of fxn (oncogene),
Recessive - loss of fxn (tumor suppressors)
chrom translocations (misexpression)


Describe the 2-Hit Hypothesis and "Loss of Heterozygosity"

• tumor suppressor genes act recessively, all function of the tumor suppressor gene must be lost
• many cancers arise in cells that lose one allele, and then later lose fxn of the second wt allele; LOH
• most inherited cancers are considered aut dominant, not because a single mutant tumor suppressor gene causes the cancer but because the germline mutation is followed by loss of the wt allele
• Inherited tumor suppressor mutations are considered dominant at the level of the organism but recessive at the level of the cell 

Ex: Mutations in stem cells can be "waiting for LOH event"  --> TRANSFORMATIVE


Briefly describe the mechanism of colorectal cancer

APC mutation – causes B-catenin to be released in excess, txn of genes like Myc
• Other mutations follow, but APC is rate-limiting 


Use DL B-Cell Lymphoma to indicate the importance of distinct disease classification 

• Diseases w/ diff genetics but same symptoms have been “lumped” together, to dvlp better treatments, we need to “split” them•

Ex: Classification of DL B-cell Lymphoma

o DLBCL is the most common form of non-Hodgkins lymphoma

o researchers created a “Lymphochip," analyzed a set of DLBCL in 42 patients and found they could group the cancers into two classes based on their stage of differentiation
o patients with “germinal center B-cell DLBCL” – survived w/chemo
o patients with “activated B-cell like DLBCL” – didn’t survive w/chemo


Give an example of a Protein-Treatment success story involving a genetic disease

Gaucher's (Lysosomal Storage Disease):  Glucocerebroside accumulation in cells (MACROPHAGES-Gaucher Cells)


Compare the two Gene Transfer strategies

o Ex vivo: transfer of a gene outside the body or a stem cell – select for what you want – reintroduce to body (ex: bone marrow)
• Advantage: doesn’t require an efficient way to enter cell
• Disadvantage: difficult & time consuming

o In vivo: direct injection into the body using a vector
• Advantage: quick & easy
• Disadvantage: targeting proper cells, immune responses, safety
• Vectors needed to introduce gene to cell
• Ideal vector should be safe, easily introduced to target cell & promote expression of transferred gene for the life of the cell
• No perfect vector yet!
• Can be viral, non-viral
o Retroviruses, adenoviruses, adeno-associated viruses, herpes viruses
o Naked DNA, liposomes, artificial chroms, protein-DNA conjugates


List and Compare the virus vectors used for gene transfer

o Include onco-retroviruses & lentiviruses, can be made to enter virtually all target cells
o Can be made simple & replication-defective / easy to engineer
o Introduce DNA into host genome!!
• Makes DNA change permanent
o Can accommodate large transgenes – helpful in therapy
o Problem: some require dividing cells to introduce DNA into genome
• Lentiviruses (like HIV) can integrate DNA into non-dividing cells
o Main problem – safety – cancer

o Advantages: can be generated at high titer – can infect wide range of cell types – can accommodate large genes…good ex is p53, Rb
o Disadvantages: does not integrate into genome so expression is transient (need constant treatment), causes strong/damaging immune response, can result in toxicity of normal cells

***** Adeno-ass. viruses (AAV)most common used today
o Advantages: similar to AV – no adverse effects in ppl (no immune response), can infect dividing & non-dividing –mostly episomal but some do integrate into host genome
o Disadvantages: until recently could only package small transgenes but… always are improvements!



1. Define neoplasia, and explain the differences between benign and malignant neoplasms.

Neoplasia means “new growth” = Neoplasm = Tumor
“A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which invoked the change.”
Malignant = spreads in body


2. Define hypertrophy, hyperplasia, metaplasia, hamartoma, dysplasia, and carcinoma in situ.

Hypertrophy: increase in the size of cells
Hyperplasia: increase in the number of cells, will stop when growth signal stops
Metaplasia: reversible change one cell type to another
Hamartoma: non-neoplastic disorganized aggregate of mature tissues indigenous to the site of origin (some are actually neoplasms!)
Choristoma: a heterotopic rest of mature cells (e.g. pancreatic tissue in submucosa of stomach)

Carcinoma In Situ (CIS) : early stage in cancer characterized by the absence of invasion into surrounding tissue through penetration of the basement membrane.  In the cell neoplastic cells proliferate in place.. Thus the term "In Situ"

*NOTE: growth is described as pre-neoplasmic which typically BUT NOT ALWAYS arises from metaplastic epithelium 


3. List the six main categories of neoplasms.

Tumors of epithelial origin (carcinoma)
Tumors of mesenchymal origin (sarcoma)
Tumors of hematopoietic or lymphoid origin (lymphoma)
Tumors of melanocytic origin (melanoma)
Tumors of the CNS (glioma)
Tumors of germ cell origin (seminoma)


4. List the three pathways of metastatic spread.

• Direct seeding of body cavities or surfaces (e.g. seeding of peritoneal, pleural, pericardial, subarachnoid)

• Lymphatic spread: carcinomas, the lymph node involvement follows the natural routes of lymphatic drainage. While worrisome for metastases, enlargement of lymph nodes in proximity to a malignancy could also be reactive.

• Hematogenous spread: sarcomas and carcinomas; carcinomas show preferential seeding of certain organs (e.g. lung carcinoma will preferentially metastasize to brain, bone, liver, adrenal). 


5. List the three most common cancers in men and women, and the one cancer responsible for most cancer deaths.

Cancer in Men: Prostate, Lung, CRC = LUNG = DEATH
Cancer in Women: Breast, Lung, CRC = LUNG = DEATH


6. Discuss the relative role that aging, environment, and genetics play in the risk for developing cancer.

• Environmental factors appear to be more significant in most common sporadic cancers.
o exposure to UV light, work exposures, high-fat diet, alcohol abuse, cigarettes, exposure to HPV

Age - Most carcinomas occur in older ppl
o cancer is primary cause of death among women aged 40 to 79 and men aged 60-79 (although CV disease is #1 overall)
o The rising incidence of cancer with age can be explained by the accumulation of somatic mutations and the decline in immune competence.  In children the types of cancers that cause death are different than adults, and carcinomas are very rare. Instead, 60% of childhood cancer deaths are due to acute leukemias and primitive CNS malignancies


7. List the four types of genes typically mutated in cancer.

  1. • growth-promoting proto-oncogenes
  2. • growth-inhibiting tumor suppressor genes
  3. • genes that regulate programmed cell death (apoptosis)
  4. • genes involved in DNA repair


8. Using only a few sentences for each, list the 8 essential alterations involved in malignant transformation of cells.

  1. • Self-sufficiency in growth signals (proliferate without external stimuli)
  2. • Insensitivity to growth-inhibitory signals
  3. • Evasion of apoptosis
  4. • Limitless replicative potential (avoid senescence – preserve telomeres)
  5. • Sustained angiogenesis
  6. • Ability to invade and metastasize (tumor metastases depend on processes that are intrinsic to the cell or are initiated by signals from the tissue environment)
  7. • Defects in DNA repair
  8. • Escape from immune attack


9. Describe examples of chemical and radiation carcinogenesis.

• Chemical carcinogenesis occurs through a multistep process (ex: Ras, p53)
o exposure of cells to a carcinogenic agent, causing permanent DNA damage (mutation)
carcinogen can signal prolif of cells
o exposure to a promotor, enhance the prolif of damaged/mutated cells
o development of additional mutations, malignant tumor

• Radiation carcinogenesis
o Caused by: Ionizing electromagnetic radiation (x-rays, gamma rays), particulate radiation (alpha particles, beta particles, protons, neutrons), UVB light
o Cancers were seen after WWII atomic bombs, after radiation treatment, carcinomas/melanomas from UV light (TT dimer)


10. Explain how the Warburg effect is used for cancer diagnosis.

Cancer cells shift their glucose metabolism to aerobic glycolysis (Warburg Effect). This metabolic change can be used to visualize tumors via positron emission tomography (PET) scanning, in which patients are injected with 18F-flourodeoxyglucose, a non-metabolizable derivative of glucose that is preferentially taken up into tumor cells as well as normal, actively dividing tissues. 


11. Define cachexia and paraneoplastic syndrome.

Cachexia: refers to the progressive loss of body fat and lean muscle mass along with weakness and anorexia that is associated with cancer. There is some correlation between the tumor burden and the degree of cachexia.
• Affected indiv have an increased metabolic rate despite reduced food intake (in contrast to starvation)
• Cachexia is not caused by the nutritional demands of the tumor, but due to action of soluble factors (tumor necrosis factor) that result in a catabolic state along with a suppressed appetite

Paraneoplastic Syndrome: Symptom complexes in cancer-bearing indiv that cannot be explained, either by spread of tumor or by the elaboration of hormones from tissue from which the tumor arose.
• They occur in about 10% of persons with the disease, a may represent the first clinical manifestation of an occult malignancy. They can even be fatal.
• Note that hypercalcemia due to skeletal (bone) metastases is not a paraneoplastic syndrome.


12. Define grading and staging of malignant neoplasms in just a few sentences. Describe what T,N,M refer to in the AJCC staging classification scheme.

Grading and staging - an attempt to quantify the aggressiveness and extent and spread of the cancer in a patient

• Grading - based on the degree of differentiation of the tumor cells, the number of mitoses and/or architectural features as seen by light microscopy
o Grade can be expressed numerically (1-3, 1-4) or descriptively (well differentiated, moderately differentiated, poorly differentiated).

• Staging - based on the size and/or local degree of invasion, extent of spread to lymph nodes, and presence or absence of distant blood borne metastases.
o The major staging classification scheme used in the United States is the American Joint Committee on Cancer Staging (AJCC). AJCC staging uses the TNM classification – T for primary tumor, N for regional lymph nodes, and M for metastases.
o Used more often than grading


13. Describe the first step in the pathologic diagnosis of neoplasms.

Step 1: Morphologic examination, coupled with ancillary studies when necessary. Obtaining a sample containing the tumor is the first step in pathologic diagnosis – biopsy, blood sample, etc.


14. In just a few sentences, describe how an immunohistochemical stain works and how flow cytometry works.


Immunohistochemistry – detection of cell products or surface markers on formalin fixed, paraffin embedded tissue(Abs w/marker). These stains are used in the diagnosis or management of malignant neoplasms as follows:
• Categorization of undifferentiated malignant tumors
• Determination of the site of origin of a tumor
• Detection of molecules that have prognostic or therapeutic significance

Flow Cytometry  - quantification of cells (incubated w/fluorescent Abs) in a stream of fluid by passing them by an electronic detection device. As the cells are detected, allows quantification of subpopulations expressing the antigen of interest.
• This technique is very useful in the identification and classification of leukemias and lymphomas


15. Describe in just a few sentences the applications of molecular diagnostics with regard to cancer – i.e., how are these techniques used?

Diagnosis of malignant neoplasms:
• Detection of specific genetic abnormality (sarcomas, hematopoietic tumors)
• B cell iG and T cell receptor gene rearrangement studies (determine B/T cell malignancies)
• DNA microarrays – determine source/type when unknown origin

Prognosis of malignant neoplasms:
• Specific chromosomal abnormalities can be associated with a better or worse prognosis in certain malignancies

Detection of minimal residual disease (e.g., ALL, CML).

Diagnosis of a hereditary predisposition to cancer (e.g. BRCA1 or BRCA2 in breast cancer).


16. Describe the common, major limitation of cancer biomarkers.

• Concept: malignant cells secrete a protein into blood or body fluids which can be measured

• Problem: biomarker is often secreted in both malignant and non-malignant conditions
o the use of tumor markers cannot be used for definitive diagnosis of cancer, but in selected situations can assist in screening for cancer

• Tumor markers can be helpful for monitoring cancer treatment as well as cancer relapse. Success: no more biomarker. Recurrence: return of biomarker 


17. Define prevalence, sensitivity, specificity, and predictive value of both positive and negative tests.


Prevalence: percentage of individuals who have the disease in the population that is tested.
Sensitivity: percentage of individuals with the disease who have a positive test result.
Specificity: percentage of individuals without the disease who have a negative test result.

As no test has perfect sensitivity and specificity, there is a tradeoff. Increasing sensitivity will decrease specificity, and vice versa. When the risk for failure to diagnose is high, you want a test with high sensitivity. Quite often a high sensitivity test is performed first (no false negatives), and this is followed with a confirmatory test that has high specificity (no false positives).