Genes, genetic disorders, and Cancer Oh my!

29. Identify and describe the following complex multifactorial diseases: Alzheimer disease, alcoholism, schizophrenia, and bipolar disorder

-AD-responsible for 60-70% of progressive cognitive decline. Risk doubles with first degree relative. Heterogeneous disorder and attributed to mutations in any 3 genes. EOAD- mutation on chromosome 21 -ETOH-3-5 times or likely if parent has ETOH. Allele ALDH2 gene responsible for ETOH metabolism (flushing, nausea, palpitations). Also genes that encode the GABA receptors. -Schizo- emotional disorder that is characterized by delusions, hallucinations, retreat from reality, recurrence lifetime risk of one effected offspring is 8-10%. An individual with a parent and a sibling has a 17 % RR. -Bipolar- incidence is 5-10% in people with a first degree relative. Genes encode monoamine oxidase A, serotonin transporter, ad catechol-O-methyltransferase (also associated with schizo)

28. Identify and describe the familial tendencies and contributing environmental factors in the following diseases: coronary artery disease (CAD), hypercholesterolemia, hypertension, colorectal cancer, diabetes, breast cancer, and obesity

-CAD-pt with family HX has a 2-7 times more likely. Risk increases w/increase # of family members and if they are female. Lipoproteins and familial hypercholesterolemia. Smoking and obesity -Familial hypercholesterolemia- most common autosomal dominant disorder. LDL is taken into cell by LDL receptors, in this disease, there is a small number of receptors. -HTN- 20-40% of the variation of SBP/DBP are genetic. Focus is on RAS, vasodilators, and ion transport systems. Increased Na+ intake, decreased physical activity, stress, and obesity. -Colon CA-1:20 will develop CR CA. clusters in families. Risk increases with first degree relative is 2-3 times more likely. APC gene encodes a tumor suppressor. ALso high fat, low fiber diet -Breast CA-double risk if has one first degree affected family member. Risk increases with age. Autosomal dominant form BRCA1 (50-80& lifetime risk) and BRCA2 -DM- type 1. siblings have an 6% risk. HLA systems account for 40% of familial clustering of DM1. Other genes have been found recently that increase susceptibility of DM1 and more susceptible to other autoimmune diseases. -Type2- TCF7L2-50% increase of developing DM2. risk factors are obesity and family HX. -Obesity-BMI>30. evidence that hereditary in adoption studies. Genes that encode leptin and its receptor.

26. Describe the genetic abnormalities and resulting clinical abnormalities associated with the following diseases: Down syndrome, Turner syndrome, Klinefelter syndrome, cri du chat syndrome, cystic fibrosis, hemophilia, and Duchenne muscular dystrophy

-DS- Trisomy 21; IQ 25-70 low nasal bridge, epicanthal folds, protruding tongue, and flat/low set ears, hypotonia and short stature, decrease ability to fight URI and increased risk of leukemia (also AD like symptoms because it is located on the same gene) -Turners- sex form of aneuploidy called Trisomy X. only one X (no X or Y pair) and only females are affected because of the lack of the Y. Sterile, gonadal streaks instead of ovaries, susceptible to CA, short, webbing of the neck in about 1/2 cases narrowing of the aorta, newborn foot edema, sparse body hair -Klinefelter- At least two XX and a Y. Usually have a male appearance, sterile, may have female like breasts.Testes are small, body hair sparse, high pitched voice. 1:1000 male births. -Cri du Chat- broken chromosomes and loss of DNA (deletion) cry of the cat, low birth weight, mental retardation, microcephaly heart defects, facial appearance -CF-autosomal recessive. 1:2500 births Protein products that forms chloride channels in the membranes of specialized epithelial cells leads to salt imbalance. Thick secretions, digestive organs become (pancreas) become clogged leading to malnutrition and respiratory and heart failure. -hemophilia-X linked and therefore passed down from mother. excessive bleeding and bruising. -DMD-Severe form of X linked disorder. 1:3500 males progressive, unable to walk by age 10-12, most die before age 20 due to respiratory and heart failure. DMD is the largest gene found in the human body (2 mill+ DNA bases) which encodes dystrophin.

23. Define and describe the following elements of inheritance: autosomal, sex-linked, carrier, dominant, and recessive.

-autosomal-sex chromosomes -sex-linked-diseases that are linked on sex chromosome (XY: hemophilia) -carrier- a person that has a gene but that is does not express the characteristics of it (MD)

18. List the cause and possible outcomes for the following mutations: base-pair substitution, frameshift substitution, spontaneous mutation, and mutational hotspots

-base pair substitution- when one base pair is replaced by another (missense mutation). Single switch in AA -frame-shift- involves the insertion of deletion of one or more base pairs to the DNA and "shifts" the while reading frame. -spontaneous- occurring randomly (not inherited) -mutation hotspots- certain DNA sequences have high mutation rates. sequences followed by CG

20. Describe the following deviations in normal chromosome structure: deletion, duplication, inversion, translocation, and fragile sites

-deletion-broken chromosomes and loss of DNA (cri du chat)-more harmful -duplication-extra genetic material -inversion-occurrence of 2 breaks on a chromosome, followed by the reinsertion of the missing fragment at its original site but INVERTED: do not result in loss of information and no apparent physical effect -translocation-interchanging of genetic information b/t nonhomologous chromosomes (robertsonian) -fragile sites-number of areas on chromosomes develop microscopic breaks and gaps, no apparent relationship to disease (Fragile X syndrome)

19. Define and give examples of the following chromosome terms: euploid, haploid, diploid, polyploidy, aneuploid, trisomy, partial trisomy, monosomy, disjunction, nondisjunction, and chromosomal mosaics.

-euploid- multiple of the normal chromosomes (normal gametes are haploid and st somatic cells are diploid) -haploid- half the chromosomes (during meiosis) -diploid- containing two complete sets of chromosomes (one from each parent) -polyploidy- when it has more than the diploid number (triploidy -3 sets and most aborted) -aneuploidy- don't contain a multiple of the 23 chromosomes (three copies of one chromosome-DS) -trisomy-3 copies of one chromosome -partial trisomy- only one extra portion of a chromosome is present in each cell. Consequences are not as severe and may occur in only part of the body. -monosomy-presence of only one copy of a given chromosome in a diploid cell (lethal) -non-disjunction-failure of chromosomes operate during mitosis -chromosomal mosaics-presence of two or more populations of cells that developed from one fertilized egg

17. Define/describe genome and genetics, replication, transcription, translation

-genome- organism's complete set of DNA, all it's genes -genetics- study of genes -replication-breaking the weak hydrogen bonds b/t pairs and leaving the single strand with each base unpaired. -transcription- process in which RNA is synthesized from a DNA template. Formation of mRNA and continues until a DNA sequence (termination sequence) is reached. -translation- RNA directs the synthesis of a polypeptide. MRNA cannot code directly from amino acids, so it interacts with transfer RNA.

27. Compare and contrast the concepts of incidence, prevalence and relative risk

-incidence- number of new cases reported during a specific period (usually 1 year) -prevalence-the proportion of the population that is affected by the disease at a specific point in time (determined by both the incidence rate and length of survival: AIDS) -relative risk- con measure of a specific risk factor (cigarette smoking and lung cancer)

7. Relate chronic inflammation to cancer cell development

-may create an environment in which cells can develop into a malignant phenotype and may even benefit progression and spread of malignancies. -noted for 150 years as a cause for CA - GI, prostate, thyroid gland, pancreas, bladder, pleura, and skin are more susceptible to oncogenic effects -in both, inflammatory cells (neutrophils lymphocytes, and macrophages) migrate to the site of injury and release cytokines, growth, and survival factors that stimulate local cell proliferation and new blood vessel growth to promote wound healing by tissue remodeling -release ROS -increased COX2 which generates prostaglandins during acute inflammation (colon CA): NSAIDS which reduce COX2 have been shown to reduce colon CA

21. Define and give examples of the following genetic terms: progeny, chromosomes, gene, allele, gamete, homozygous, heterozygous, dominant traits, recessive traits, pedigree chart, penetrance, and expressivity.

-progeny-descendants of a person -chromosomes- thread like structure located inside the nucleus of the cell. -gene- locus of DNA that encodes a functional RNA or protein -allele- variant form of a gene -gamete- mature haploid male or female germ cells -homozygous- inheriting the same alleles for a particular gene from both parents (AA) -heterozygous- inheriting different alleles (Aa) -dominant- effects that are observable (A-brown eyes) -recessive-effects that are not observable (Aa-blue-CF) -pedigree-chart to summarize genetic inheritance -penetrance- extent of which a particular gene is expressed in the phenotypes of the person carrying it (incomplete-retinoblastoma 90% of people with trait express it) -expressivity-the extent of the variation of the phenotype associated with a particular genotype (NF type 1)

25. Evaluate the recurrence or occurrence risk for the single-gene inheritance patterns, given the maternal and paternal genotype and/or the Punnett square

-recurrence risks- risk of child having disease when both parents are heterozygous carriers (25%)

1. Define tumor, neoplasia, and cancer

1) tumor- abnormal growth resulting from uncontrolled proliferation and serves no function 2) neoplasm- a new growth, either benign or malignant-may still be life threatening 3) cancer- refers to a malignant tumor and is not uses to refer to benign growths, such as lipomas or hypertrophy of an organ.

11. Identify and describe the common clinical manifestations of cancer: anemia, leukopenia, thrombocytopenia, infection, paraneoplastic syndromes, fatigue, and pain.

BOX 12-2 pg. 396

13. Compare and contrast the modalities for the treatment of cancer: chemotherapy, surgery, radiation, and immunotherapy.

CHEMO: started in the WWII with mustard gas and suppressed bone marrow. -folic acid increase leukemia and thus began methotrexate -anti-metabolites-block normal growth pathways in all cells but CA cells are typically more sensitive -single chemo usually shrink tumors but rarely provide a cure. 1)induction-cause shrinkage or disappearance of tumors. Hodgkin's, chemo may cure 2) adjunctive- given after surgery to eliminate micrometastases. 3) neo-adjunctive-given before surgery or radiation to shrink the tissue to help spare normal tissue. SURGERY: biopsy or often the definitive TX of CA that do not spread beyond the limits of the surgical excision. -indicated in the relief of symptoms (mass obstruction) 1) obtain adequate surgical margins to prevent local recurrences 2) placing needle tracks and biopsy scars so they cn be removed with subsequent incisions 3) prevent the spread of CA with careful technique 4) and obtaining specimens for diagnosis and staging.

2. Cite the method for naming and classifying benign and malignant tumors; provide examples

Classification starts with knowing the site of origin, microscopic appearance of the lesion, and can extend to a detailed description of the critical genetic changes in the cancer. benign- usually encapsulated and well differentiated. Do not invade surrounding or spread. "-oma" (lipoma) malignant- progress to cancer; rapid growth, loss of differentiation and absence of normal tissue organization; anaplasia-loss of cellular differentiation -different degrees of encapsulation -named according to the cell type from which they originate -ability to spread far beyond the tissue of origin -cancer in situ- preinvasive epithelial malignant tumor of glandular or squamous cell origin.

16. Describe the composition of DNA

DOuble helix: consisting of proteins (histones) 4 nitrogenous bases: adenine, cytosine, guanine, and thymine -pairs= nucleotide

10. Describe the World Health Organization's TNM system for tumor staging

FIGURE 12-5 pg 394

3. Define tumor cell marker (TCM); cite marker examples that suggest the existence of cancer. What are the advantages and disadvantages of tumor cell markers?

Tumor marker- substances produced by both benign and malignant cells that are either are present in or n tumor cells or are found in blood, CSF, or urine. ex: 1) alpha fetoprotein-liver and germ cell tumors 2) PSA- prostate paraneoplastic- when tumor marker itself has biologic activity and can cause symptoms (adrenal medulla tumors producing adrenaline in vast excess) GOOD: screen and ID high risk people, help diagnose the specific type of tumor in individuals with clinical manifestations relating to the tumor, and follow the clinical course of a tumor. BAD: screening people will detect pts with high end norals "false positives", which can lead to expensive and invasive tests; also some non-malignant tumor can produce tumor markers.

22. Differentiate between genotype and phenotype

genotype- composition of genes at a given locus phenotype-the outward appearance of an individual

5. Compare and contrast the gene products of proto-oncogenes, oncogenes, and tumor suppressor genes.

oncogenes- mutant genes that in normal non-mutant state direct the synthesis of proteins that accelerate proliferation -chromosome instability and increased rates of mutation proto-oncogene- is an oncogene in normal (non-mutant state)-GF tumor suppressor genes- encode proteins that in normal state negatively (halt) regulate proliferation. -requires loss of function of both alleles to increased cancer risk

6. Describe how the following genetic events can activate oncogenes: point mutations, chromosome translocations, gene amplification, tumor suppressor gene mutation, and loss of heterozygosity.

point mutations- most common; the alteration d one or a few nucleotide base pairs - EX: if occurs in ras gene, it converts to unregulated , an accelerator of cell proliferation (pancreatic and colorectal CA) chromosome translocations-large changes in the chromosome structure. A piece of one chromosome is translocated to another chromosome. 1) cause excess and inappropriate production of proliferation factor (Burkitt lymphoma) 2) lead to production of novel proteins with growth-promoting properties (CML) gene amplification- result of duplication of a small piece of a chromosome (repeats). can increase expression of oncogene or drug resistant genes. -EX: epidermal growth factor receptor erb2 is amplified in 20% of breast CA. tumor suppressor- negatively regulate cell growth and prevent gene mutations by slowing cell cycle, inhibit proliferations, or stop cell division. Can be inactivated by a single genetic event. Both chromosomal copies must be inactivated (allelles) -EX: retinoblastoma (Rb) gene-when inactivated, cell division can go unchecked. loss of heterozygosity- loss in one copy of a chromosome region in a tumor. -Can unmask inactivating mutations in recessive tumor-suppressing genes.

12. Characterize the syndrome of cachexia

syndrome that includes many symptoms including anorexia, early satiety, weight loss, anemia, marked weakness (asthenia), taste alterations, altered protein lipid, and carb metabolism.

4. Describe gene mutations that alter tumor growth signals

transformation- process of cell becomes CA autonomy- CA cells independence from normal cellular controls -lack contact inhibition-continue to crowd and pike on each other. -anchorage independent-continue to divide even when suspended in soft agar gel (not firmly attached like normal cells) -immortal- seem to have unlimited life span and will divide for years -lack differentiation- meaning don't need to specialize to become specific type of cell.