BLD 204 Exam 4

neoplasms

"new growth" Abnormal, mass of tissue.
Fundamental characteristics of all cancer:
Disorderly cells
-cell proliferation
-cell differentiation
-relationship to the surrounding stroma.

tumor

in neoplasms, often is referred to as a tumor.

carcinogenesis

initiation of cancer formation.

oncology

study of tumors.

Assess whether a neoplasm is benign or malignant using all of the proper criteria.

Benign:
-don't invade surrounding tissue.
-no metastasis
-growth rate low
-little mitosis
-some atrophy of surrounding tissue by pressure of the mass.

Malignant:
-invade surrounding tissue
-metastasis
-lots of mitosis and growth
-damages surrounding tissue
-invasiveness
-abnormal tissue formations
-increased proliferation. abnormal cell division
-incomplete differentiation: cells vary in size and shape, nuclei have greater volume than normal in proportion, abnormal ploidy.

Describe the morphologic changes associated with anaplasia

-malignant neoplasms that are composed of undifferentiated cells are said to be anaplastic.
-lack of differentiation, loss of the structural or functional differentiation of normal cells.
-anaplastic cells display marked pleomorphism. (variation in size and shape)
-often nuclei are variable and bizarre in size and shape.
-Giant cells.
-cells lose normal polarity.

compare and contrast metastatic neoplasm with dysplasia

Dysplasia:
-cell changes indicative of malignancy but no invasion present yet.
-its a warning sign
-common in epithelial tissue: malignant: carcinomas.
-if the whole depth of the tissue is dysplasia, then the term carcinoma in situ is used.
Connective tissue: malignant, sarcoma
-disorderly but non-neoplastic proliferation
-loss in the uniformity of individual cells and in their architectural orientation.

Metastatic neoplasm:
-secondary implants of a tumor that are discontinuous with the primary tumor and located in remote tissues.
-identifies a neoplasm as malignant.

Describe hamartoma, heteroplasia, and choristoma and differentiate between those conditions and true neoplasms

Hamartoma:
-tumor-like mass
-lacks autonomous behavior
-good differentiation and in the right organ
-organization is different from normal
-vascular most common

Heteroplasia:
-differentiation of tissue is wrong for location
-NOT METAPLASIA, no change from one fully differentiated form to another.
-happens at the stem cell stage
-just a mass that doesn't belong there
-masses of various types or one type of tissue
(choristomas: congenital)

Choristoma:
-congenital anomaly consisting of a heterotypic rest of cells. Ex. a well developed pancreatic tissue might be found in the submucosa of the stomach.

compare and contrast papillomas and adenomas

Papillomas:
-epithelial cells growing in a sheet
-squamos, transitional or columnar
-benign epithelial neoplasms growing on any surface that produce microscopic or macroscopic finger-like fronds.
Adenoma:
-solid islands or masses of cells
-arising from gland or duct epithelium.
-benign epithelial neoplasms producing gland patterns
Adenoma development:
-because of the source tissue, small groups of cells gather around a lumen
-But there is no real drainage, so a cyst may develop (cystadenoma)

compare and contrast carcinoma and sarcoma

Sarcoma:
-malignant neoplasms arising in "solid" mesenchymal tissues or its derivatives are called sarcomas.
-designated by cell type of which they are composed of which is usually their cell of origin.
Carcinoma:
-malignant neoplasms of epithelial cells
-regardless of tissue of origin.
-can be divided further into glandular patterns called adenocarcinomas.

contrast neoplastic differentiation defects with metaplasia.

metaplasia:
-abnormal change in the nature of the tissue.
Neoplastic differentiation defects:
-neoplastic cells fail to differentiate properly.
-they often remain "stuck" in more immature states.
-immature, undifferentiated cells exhibit behaviors that they shouldn't like expressing fetal proteins or hormones.
-benign masses expand into space where they don't belong.
-malignant neoplasms spread into surrounding tissues and even to other parts of the body.

compare and contrast normal cell adaptations to stress to neoplastic growth

Normal cells:
-recognize each other
-communicate about divison
-adhere to each other
-non neoplastic changes cease when the stimulus is removed.
Neoplastic:
grow on top of one another
don't respond to normal stimuli
have a failure of inhibition signals that would restrain proliferation
or
increased growth factor expression encourages them to proliferate (autocrine) Ex. TNF-a, PDGF
or both things happen

discuss physiological negative feedback loops

Hyperplasia: (more cells and can get big) a response to an increase in functional need. controlled by negative feedback mechanisms
Normal:
Change detected-->corrective mechanisms turned off--> normal conditions return-->switch off corrective mechanisms-->change from normal
Feedback loop:
Change from normal-->change detected-->switch off corrective mechanisms--> normal conditions return
Hypertrophy:
-The cells get Bigger
atrophy:
decrease in bulk due to decrease in demand

Two examples of hyperplasia

1. congenital adrenal hyperplasia
-early manifestations
-masculization of females
-early puberty for males
-salt loss
What happens:
-defective adrenal cells: decreased cortisol and aldosterone. increased adrenocorticopic hormone from pituitary.
make more adrenal cells which still don't work. Built up precursors of hormones get used for steroid production instead.
2. Thyroid hyperplasia
-two causes: abnormal stimuli, problem with feedback for TSH. (more TSH= more hyperplasia)

Discuss each phase of cell cycle

G1:
not resting like G0
depends on cell type, can be a long cycle
cells that remain in the cycle are termed being in the growth fraction
S
DNA synthesis occurs in this place
G2
premitotic phase
M
actively undergoing mitosis

name the enzyme groups which control the cell cycle.

-cyclins
-cyclin dependent kinases
-CDK inhibitors.

Discuss self-sufficiency of growth signals (hallmark of cancer)

1. self-sufficiency of growth signals.
-five steps to cell proliferation.
Growth factors and receptors:
-paracrine is most growth factor action on normal cells.
-cancer cells make their own or they tell the stroma to make them some.
Receptors:
-cancer cells overexpress these receptors.
-or the y have mutated receptors that are always on sending signals continuously even without growth factor.
Example:
overexertion of EGF
-80% of squamos cell carcinomas of lung
-50% glioblastomas
-80-100% of epithelial tumors of head/neck
Similar overexertion of ERBB2
-25-30% of breast cancers
Signal Tranducing Proteins:
-mutations occur further downstream, on the signally proteins inside the cell
-direct stimulation of signal to the nucleus without growth receptor signal
-two most common mutations are in RAS and ABL
Self sufficiency of proliferation is opposed by other cellular pathways
-senescence
-apoptosis
These need disabling too. one hallmark is not enough.

Explain RAS and ABL in self sufficiency of growth signals

RAS
-most commonly mutated gene in human tumors
-small protein that binds GTP, GDP
ABL
-tyrosine kinase
-translocation in chronic myelogenous leukemia from chromosome 9 to 22
-fuses with BCR there and makes fusion protein that has constitutive activity.

Self sufficiency of growth signals: nuclear transcription factors

Transcription:
-transcription factors regulate expression of pertains by controlling transcription of DNA
-cancer-related mutations in TFs can result in expression of more growth promoting genes like growth factor genes

MYC
-activate or repress
-activates genes that encourage progression through the cell cycle like cyclins
-represses genes that repress genes that prevent it
-encourages aerobic glycolysis and glutamine utilization
-Burkitt's lymphoma

Describe self sufficiency of growth signals: cyclins and cyclin- dependent kinases

-Cyclins: regulate progression through the cell cycle
-Cyclin Dependent kinases: activated by binding to cyclins, maintain orderly progression
-Cyclin dependent kinase inhibitor: broad and selective inhibitors of CDKs
-Alterations in cancer cells:
all cancers seem to have mutations that disable the G1-S checkpoint
Increased cyclin D and CDK4 expression
CDKIs disabled by mutation or silenced

Insensitivity to Growth inhibition signals: hallmark of cancer

-Tumor suppressor genes: "brakes" for proliferation
-the result of mutations in this system is very similar to self-sufficiency of growth signals
four major targets:
-RB (the governor)
-TP53 (the guardian)
-TGF-Beta
-Contact inhibition pathways

Insensitivity to growth inhibition signals: RB

-DNA-binding
-regulates the G1-S checkpoint
-important in development, cell cycle "clock"
-once past, they must divide eventually
-fairly common mutation
-many viruses which are oncogenic bind RB
-This is the gene implicated in retinoblastoma, rare in childhood cancer

Insensitivity to growth inhibition signals: TP53-beta pathway

-NORMAL proliferation inhibitor in epithelial, endothelial, and hematopoietic cells
-Mutations in 100% of pancreatic cancers and 83% of colon cancers

What do transformed cells do? in insensitivity to growth inhibition signals: contact inhibition

the don't show contact inhibition in cell culture

Contact inhibition in insensitivity to growth inhibition signals

-Cadherins mediate cell-cell contact
-NF2 gene product merlin facilitates E cadherin contact inhibition
-APC gene product loss also can be involved in loss of contact inhibition by destroying B-catenin which can be a growth- promoting transcription factor. (APC is a condition where patients get lots of polyps)

Evading apoptosis

-two apoptotic pathways: intrinsic and extrinsic
-both result in activation of caspase cascade
-BAX-BAK pro apoptotic action is regulated by BCL2 which is anti apoptotic
-BCL2 mutations that activate it are common in B cell lymphomas
-cancer cells also avoid autophagy by mutation or take it over to get "parts" to grow

Limitless replicative potential

-Max # of divisions is usually 60-70
-then senescence occurs
-due to telomere shortening.
-short telomeres are recognized as dsDNA breaks leading to senescence mediated by RB and p53
-If RB and p53 are inactivated, then the ends of two chromosomes get connected in a last ditch effort at repair
-leads to dicentric chromosomes

Limitless replicative potential : shortening and aging cells

-another option: bring back telomerase
-telomerase is usually only present in stem cells, maintains telomere length
-telomerase can be reactivated to maintain telomere length in cancer cells (85-95%)

limitless replicative potential: model

-constant proliferation leads to telomere shortening.
-telomere shortening leads to bridge-fusion-breakage cycle when p53 is absent
-BFB cycle leads to mutations
-Telomerase is reactivated, fixing mutations and allowing the cells to continue dividing.

Development of sustained angiogenesis

-tumors need food and oxygen too.
-tumors bigger than a 2mm can't survive without vascularization
-must be able to induce angiogenesis, both benign and malignant tumors

How are tumors vascularized?
-neoangiogenesis: new sprouts from capillaries in the area
-vasculogenesis: endothelial cells come from the bone marrow to make blood vessels
-decrease of hypoxia, production of angiogenic factors= inhibitory factors (angiogenic switch)

Development of sustained angiogenesis: Hypoxia

-normally, hypoxia stimulates production of pro-angiogenesis cytokines like VEGF
-this happens through activation of HIF-1a
-unless there is hypoxia, HIF-1a is controlled by VHL which binds it signaling for its destruction
-if there is hypoxia, VHL no longer binds HIF-1a

Development of sustained angiogenesis: Angiogenic factors and inhibitory factors

Angiogenic:
-vascular endothelial growth factor (VEGF)
-FGF released from ECM by proteases

Inhibitory:
-Thrombospondin-1 (TSP-1): produced by stromal fibroblasts and synthesis is induced by p53
-Protease-produced angiostatin, endostatin, and vasculostatin

Development of sustained angiogenesis: Cancer

-losing p53= lose TSP-1
-VHL mutations associated with renal cancers
-cancer cells produce VEGF and proteases that can swing the balance.

Ability to invade and metastasize

-invade surrounding tissues by dividing in place
-metastatic spread by lymphatics or blood stream

Metastasis:
-2nd tumor site with no continuity with the first
-spread via the lymphatics
-spread via the blood stream

Lymphatic spread:
-Most common in carcinomas. Ex. carcinoma of the breast, malignant melanoma
-invades the lymphatic vessels and spreads up along the lymphatic vessel to the node.
-The blood stream and lymphatics are connected.

Spread via blood stream:
-most common in sarcomas
-invasion can happen in the tumor's new blood vessels (angiogenesis) or in nearby normal vasculature.

List the steps of metastasis and the ability to invade and metastasize

1. liberation
2. invasion
3.transfer as emboli
4.adhesion at endothelium
5. migration from the vessel
6. survival (angiogenesis)
7. multiplication and growth.

Ability to invade:
-degree of spread relates to survival
-secondary sites:
liver: most common via the blood stream
sources: GI and pancreas

Skeleton:
second most common site after liver
sources: breast, prostate, kidney, thyroid

Brain:
sources: lung most common, also breast and adrenals

Lung:
sources: breast and stomach carcinomas, sarcomas

Adrenals:
most frequent endocrine gland site.
Source: lung, breast.

describe reprogramming energy metabolism and evading the immune system as "new" hallmarks of cancer

reprogramming:
-aerobic glycolysis (warburg effect)
-favored when rapid growth is required
Evading:
-most cancer patients are immunocompetent until treatments
Carcinogenesis:
genetic basis of cancer
The key is NONLETHAL genetic damage

List and describe the function of four classes of normal regulatory genes which are the primary targets of genetic damage leading to neoplastic changes

1. Growth- promoting photo oncogenes
-Genes that induce a transformed phenotype when expressed in cells
-usually mutated or overexposed versions of normal genes-proto-oncogenes
-DOMINANT: single allele is sufficient for transformation
2. Growth-inhibiting tumor suppressor genes
-genes that normally suppress uncontrolled growth
-when they are mutated or lost, the transformed phenotype appears
-Usually, both alleles have to be damaged for the phenotype to appear but some times a single allele will do it. (haploinsufficiency)
-Two types of tumor suppressor genes:
Governors: mutation removes an important "stop" mechanism (RB)
Guardians: produce proteins that act as sensors of genomic damage (p53)
3. Genes that regulate Apoptosis
4. Genes that are involved in DNA repair
-These may act as oncogenes or tumor suppressor genes
-an example of a photo-oncogene that regulates apoptosis might be BCL2

describe the types of chromosomal lesions that can be observed in tumor cells.

Karyotype Changes
-changes in the number and appearance of chromosomes
-specific changes have been identified in particular neoplasms
1. balanced translocations
2. deletions
3. gene amplification
4.Aneuploidy
5.MicroRNA's and cancer
6. Epigenetics
7. selective pressures

Describe balanced translocations

1. translocation moves the gene to where its under an inappropriate, highly active promotor.
-MYC and Burkitt's lymphoma
-follicular B cell lymphoma and BCL2

2. Translocations make fusion proteins
-CML and the "Philadelphia" chromosome

Lymphocytes and their precursors are the most common types of cells where genome rearrangements occur.
Why?- these cells intentional make DNA breaks in rearranging their antibody or TCRs genes.

Describe deletions

-2nd most common karyotypic abnormality
-large deletions more common in non-hematopoietic solid tumors
-often tumor suppressors are deleted.
-Loss of heterozygosity
point mutation in one allele
deletion of the other
Rb or p53

Describe gene amplification

proto-oncogenes---> oncogenes
-NMYC neuroblastoma
-ERBB2 breast cancer

Describe Aneuploidy

-number of chromosomes that is not a multiple of the normal haploid number (23)
-mitotic checkpoint errors

Describe MicroRNAs and Cancers

-non-coding single stranded regulatory RNA
-increase oncogene expression
-decrease tumor suppressor expression

describe epigenetics

-epigenetics: reversible, heritable changes in gene expression
-no mutations!
-methylation of histones and DNA increase expression of genes
-cancer cells have global hypomethylation of the genome and hypermethylation of certain promoters.
-hypomethylation "silences" gene expression
-hypomethylation makes the genome unstable and leads to tumor in mice
-mutations in genes that are involved in methylation of histones and DNA have been implicated in some cancers.

Describe selective pressures

multiple genetic alterations= transformed phenotype
-tumor progression, the fact that cancer becomes more malignant with time.
-initial tumor is monoclonal, but by the time cancers reach their dangerous stage clinically, they may be very heterozygous.
-because the tumor cells are undergoing Darwinian selection
-there are immune and non-immune selective pressures acting on the cancer cells
-subclones that bear advantageous mutations out compete those that do not
-tumors that recur are more aggressive and more resistant to treatment.

Explain how epigenetic changes and microRNA mutations can be involved in neoplastic transformation.

transformation:
progression: proliferation of genetically unstable cells--->Tumor cell variants: heterogeneity

List the five factors that contribute to an individual's risk of developing cancer.

Helping malignancy along:
-both alleles must be lost but certain ones exhibit haploinsufficiency
-3 repair systems:
Problems with Mismatch repair: hereditary colon cancer syndrome
-carcinoma of the cecum and proximal colon
-mismatch repair genes "proofread" DNA to make sure mismatches don't accumulate
-at least four genes implicated
-effect isn't direct. it allows mutations in genes that contribute to the hallmarks.
Problems with nucleotide excision repair: pigmentosum
-mutations contribute to higher risk of sun-damage from UV light
-Uv cross-linking of pyrimidine is not repaired by the excision process
-several proteins involved, loss of one is enough to cause problem
Problems with recombination repair: fanconi anemia
-group of autosomal recessive disorders
-phenotypes are complex and characterized by other issues too, like anemia
-Also BRCA1 and BRCA2 in breast cancer: chromosomal breaks and severe aneuploidy

discuss regulated genome instability: lymphoid neoplasms and inflammation and malignancy

lymphoid neoplasms:
-rearrangements of VDJ genes for BCR/TCR are controlled instability
-isotype switching and somatic hypermutation
-mutations in these cells that result in neoplasm often have errors from these processes

Inflammation:
-chronic inflammation: microbial infections or autoimmune responses
-when inflammation occurs in response to tumors.
-common offenders: H. pylori gastritis, HBV, HCV
-presistent repllication and all those cytokines signaling plus ROS from neutrophils trying to kill things are major contributors to the problem.

list three categories of carcinogenic agents

1. Chemical
-mutagens, common targets are RAS, p53
-maybe augmented by promoters whose application follows the initiating mutagen
-promoters contribute to proliferation of the mutated cells

2. Radiation
-Chromosomal breakage, translocations, rarely point mutations

3. Microbial and viral
-Human RNA viruses
HTLV-1:
-TAX: triggers GF production, inhibits p53 and other inhibitors of proliferation
Tropism CD4+ cells
neoplasm in 3-5% of infected people after 20-50 years of latency

contrast direct-acting chemical carcinogens with indirect-acting agents.

Direct-acting agents
-no metabolic action is needed
-many are used for chemotherapy

Indirect-acting agents
-require metabolism of agent to become carcinogen
-products from the burning of tobacco
-broiling or smoking animal fats
-epoxides bind DNA, RNA, and protein

describe two theories of radiation carcinogenesis

1. Direct: radiation itself damages DNA
2. Radiation activates dormant viral oncogenes

List the type of cancer associated with HPV, EBV, HBV, HCV, and H. pylori infection.

HPV:
-human DNA virus
-warts and cervical cancer
-interactions with Rb, releasing transcription factors normally requested
EBV:
-first virus linked to a human tumor
-Burkitt's lymphoma and many others
-attaches to B cells through CD21
-causes proliferation and generator lympho-blastoid cell lines
HBV and HCV:
-hepatitis
-70-85% of hepatocellular carcinomas worldwide are due to infection
-many factors: chronic inflammation causes cellular injury, hepatocyte proliferation, and ROS production
H. Pylori:
-fist implicated in peptic ulcers then the first bacterial carcinogen
Mechanisms:
-chronic inflammation
-stimulation of gastric cell proliferation
-ROS that damages DNA
-CagA stimulates GF pathways
-Leads to polyclonal B cell proliferation that result in monoclonal B cell tumors

Describe how mechanical pressure or obstruction effect the host

Damage is dependent upon site versus tumor size
sometimes the pattern of spread is important.

describe how tissue destruction effects the host

breakdown of tissue can be either by pressure or invasive properties of the tumor.
Bone destruction can lead to fractures and hypercalcemia:
-related to neoplasm can have two causes:
1. osteolysis releasing bone
2. ectopic hormone production
-parathyroid hormone related peptide

describe how hemorrhage effects the host

-common in epithelial tumors and cancers of colon
-ulceration and bleeding occur, usually not dramatically
-can lead to anemia
-less commonly, serious bleeding can occur in stomach and intestinal tumors

describe how infection effects the host

Patients are susceptible to infection due to:
-blocked drainage
-ulceration
-immunosuppression

describe how fever effects the host

common in many types of malignant neoplasm
-caused by release of cytokines from the tumor cells or macrophages
-IL-1, TNF-alpha

describe how cachexia effects the host

Weight loss and wasting later in disease
contributing factors:
-anorexia
-malabsorption
-toxic products
-TNF-alpha (cachectin)

describe how anemia effects the host

lack of blood

list and describe the four categories of laboratory methods used to provide diagnosis, theranosis, or prognosis in oncology

-morphology of tissues and cells
-tumor markers
PSA, CEA, Alpha fetoprotein
-molecular diagnosis
diagnosis, prognosis and behavior, hereditary disposition, therapeutics
-molecular profiling
expression profiling, whole genome sequencing

discuss the concepts of immune surveillance and immune evasion in the context of cancer

-immune surveillance:
the immune system detects and eliminates tumor cells that have developed as a result of failed intrinsic tumor suppressor mechanisms.
-Immune evasion:
antigens are released, cancer antigen presentation, priming, and activation, Tcells travel to tumorous cells, recognition of tumor cells by the Tcells, killing of the cancer cells.

What could cancer cells do to avoid these processes?
-would keep mutating and changing their external markers and antigens to throw off the Tcells

Congenital vs. hereditary disease

A genetic abnormality acts alone. unfavorable environmental factors may contribute
Congenital: present at birth
Hereditary: passed on genetically from parent to offspring

genotype

What the genetics are, what the DNA code is:
-your genome encodes a particular allele

phenotype

the observable outcome of the code
-the allele gives you blue eyes

karyotyping

Sources of chromosomes:
-lymphocytes, amniotic fluid, bone marrow
-cells are encouraged to enter mitosis
-chromosomes are separated from the cells
-suspension is put on slide and Giemsa stained
-makes bands on the chromosome that are used to define regions
-how you analyze whole chromosomes/ regions with mutations
chromosome number
short or long arm: p or q
group that the band is in: numbers
number of band in the group 5q34

mutation inheritance

inherited genetic alterations in cells

nondisjunction

failure of one or more pairs of sister chromosome to separate normally during nuclear division, Resulting in an abnormal distribution of chromosomes in the daughter nuclei

inversion

breaks and moving around occur in the same chromosome
paracentric: same side of the centromere
pericentric: opposite sides of the centromere

sex-linked recessive

Sex chromosomes: XY
Problem is on the X
-so for males all it takes is one copy for expression of the mutant phenotype
-females need to be homozygous for the mutant phenotype to be expressed

X-linked:
From dad
-all daughters are carriers
-all sons are fine
From heterozygous mom:
-50% of sons are affected
-50% of daughters are carriers

aneuploidy

not a multiple of 23
-trisomy: extra chromosome
-monosomy: loss of a pair
Polyploidy: additional whole haploid set (69 instead of 46)

mendelian

theory that attempts to explain inheritance and diversity.

deletion

you need to lose about 4000 kilo bases to make it visible
Gene deletions:
-a thalassemia: number of deletions relates to severity of disease
-normal Hgb requires two pairs of a globan genes
loss of two copies of a= HbH disease
loss of all copies= hydrous fettles

Partial gene deletions:
-part of the code is deleted, but some protein may still be translated
-duchenne's muscular dystrophy
-dystrophin gene partial deletion huge gene 2500 kbases
break occurs within a codon causing a frame shift.

Whole codon deletions:
-doesn't alter reading frame
-you lose an amino acid: can result in improper folding or affect function or be just fine.
Ex. cystic fibrosis: most common mutation is a deletion of one codon for phenylalanine in the gene for a chloride transporter (CFTR)

translocation

balanced
-reciprocal transfer of segments between chromosomes
-CML translocation 9-22
Robertsonian
-one very large and one very small
-long arm of one and short arm of another

list 4 different factors that are known to be associated with variations in the genetic structure

sequence and copy number variations
alterations in non-coding RNAs
epigenetic changes
multifactoral disorders

define cytogenetic disorder

1 in 200 newborns
chromosome abnormalities

Define and describe down's syndrome and klinefelters syndrome based on the following criteria:
a. cytogenetic alteration observed with karyotyping
b. proposed mechanism by which this alteration occurred
c. major clinical features of each
d. incidence of each syndrome and its relationship to age
e. life expectancy
f. prenatal screening procedures

Down's syndrome: most common cytogenetic disorder. More likely in woman 35 or older. 95% have trisomy 21 which is caused by meiotic nondisjunction.
a.
b.
c. face, hands, long bones, eye diseases, sleep apnea, hearing loss. Cardiovascular: 40% have congenital defects. Hematology: 10-20x risk of developing leukemia. Immune: increased susceptibility to infection. CNS: reduced IQ, alzheimers like symptoms in 40s
d.
e. reduced life expectancy: late 40s
f. screening: blood tests, ultrasound. Diagnosis (chromosome testing)
-chronic villus sampling: material from placenta
-amniocentesis: amniotic fluid
-Percutaneous umbilical blood sampling: umbilical cord blood

Klinefelter's syndrome:
-extra X chromosome in phenotypic male
-nondisjunction leads to XXY
-may have more than one extra X
-contributing factors:
advanced maternal age, radiation of either parent.
Clinical features:
-hypogonadism: too little testosterone, under developed genitals
-increased leg length, disportionately
-wide pelvis
-reduced facial and body hair
-gynecomastia (risk of breast cancer increased)

list and describe the types of mutations from which single gene defects may arise

-Autosomal vs. sex-linked genetic disorders
-dominant vs. recessive patterns of inheritance
-examples
-pedigrees

Describe the mode of inheritance, the specific metabolic alteration and the clinical symptoms and consequences of familial hypercholesterolemia.

LDL receptor defect (LDLRD)/can't remove LDL.
premature atherosclerosis

For each of the following inborn errors of metabolism state the mode of inheritance, the specific metabolic pathway affected, the enzyme defect, the clinical manifestations and treatment where applicable:
1. phenylketonuria

-Defect in enzyme that breaks down phenylalanine.
-build up and causes brain damage but can be treated by dietary changes
-since the 1960s, newborn screening has helped prevent problems associated

Describe the genetic basis of hemophilia A, state which clotting factor is missing and give the clinical consequences of this abnormality. State an appropriate method for treating this disorder

Factor XIII deficiency in the coagulation pathway causes bleeding problems

differentiate between an autosomal dominant mode of inheritance and an autosomal recessive pattern.

Autosomal dominant:
-frequency 2-9:1000 births
what do you see?
-parent is affected or at least heterozygous
-phenotype is expressed at the same rate in males and females see the mutant phenotype in every generation
-both heterozygotes and homozygotes express the mutant phenotype
50% reduction in gene product can be compensated for, but not less than 50%
-not usually proteins/enzymes
-regulatory proteins and structural proteins

Autosomal recessive:
what do you see?
-parents may not have mutant phenotype but siblings may have disease
-parents are at least heterozygous
-penetrance is usually complete
-frequency of mutant phenotype for males and females is equal
Genes are often coding for enzymes
Alpha 1 antitrypsin deficiency
phenylketonuria

discuss the genetic basis of cystic fibrosis and alph-1 antitrypsin deficiency

AAT suppresses proteases in the lungs. Without functional AAT, emphysema can result.
Three alleles: M, S, Z
-M is normal
-S produces a lower amount of AAT
-Z results in serious loss of AAT production

For each of the following inborn errors of metabolism state the mode of inheritance, the specific metabolic pathway affected, the enzyme defect, the clinical manifestations and treatment where applicable.
1. Galactosemia

-autosomal recessive 1:60,000
- lack of GALT enzyme which helps convert galactose to glucose
-metabolites from galactose accumulate in liver, eyes, kidneys, spleen and cerebral cortex
-first signs are vomiting and diarrhea when given milk, then jaundice
-removal of galactose from diet helps severe complications

Explain the differences between Prader-willi syndrome and Angelman syndrome in the context of genomic imprinting.

Prader-willi syndrome
-mental retardation, short stature, hypotonia, obesity, hypogonadism, deletion is paternal
prader vs. angelman
-in some cases, functional differences exist between paternal and maternal alleles of the same gene
-differences arise from imprinting, an epigenetic process.
-maternal imprinting= epigentic silencing of maternal allele
Imprinting
-methylation of gene promoter and modification of histones
-occurs in the ovum/sperm and transmitted to somatic cells derived from that zygote
Angelman:
-mental retardation
-ataxic gait
-seizures
-inappropriate laughter
-maternal deletion

Tay-Sacks disease is a lysosomal storage disease, discuss the mod of inheritance, the specific metabolic defect, the clinical manifestations and the prognosis

Gangliosidosis
-accumulation of gangliosides in brain
-gangliosides are complex molecules made up of glycosphingolipid and sialic acid
-most common in Ashkenazi Jewish populations and french canadians
-deficiency is a catabolic enzyme in the lysosome so gangliosides hang around
-mainly affects neurons where gangliosides are metabolized
-100 mutations
hexosaminidase A B subunits
levels used for detection of heterozygosity
-unfolded protein response is involved in stimulating apoptosis
-molecular chaperone therapy
-acute disease has onset at 3-6 months
progressive weakness
blindness
severe neurologic dysfunctions
death in 2-3 years