Biomed Exam 2.pdf

GENETICS Define nucleotide, codon, amino acid, and protein Nucleotide: building block of DNA / RNA, purine or pyrimidine base attached to a ribose phosphate *Nucleosides do not have phosphate* Codon: se...

GENETICS Define nucleotide, codon, amino acid, and protein Nucleotide: building block of DNA / RNA, purine or pyrimidine base attached to a ribose phosphate *Nucleosides do not have phosphate* Codon: set of 3 nucleotides that codes for a particular amino acid Amino acid: building blocks of proteins - 20 in human proteins - 9 essential - cannot be synthesized, must be provided in diet - 11 non essential - can be synthesized, not required in diet Protein: polymers of amino acids - Enzymes - carry out biochemical reactions - Structural - hold things together (collagen, keratin) - Carrier - transfer small molecules (hemoglobin, ferritin) - Receptors - bind circulating molecules (insulin, cholesterol) - Regulatory - turn genes on / off (growth factors) Explain the difference between DNA and RNA and their function DNA RNA Double stranded Single stranded Deoxyribose nucleotides (A, T, G, C) Ribose nucleotides (A, U, G, C) Repository of genetic information Short half life Replicated with cell division mRNA, tRNA, rRNA (protein synthesis) Stored as chromosomes Regulatory functions Define karyotype, autosomes, sex chromosomes, homologs, sister chromatids, and alleles Chromosomes: one molecule of DNA and associated proteins - 23 pairs (diploid) - 1 of each chromosome from mom, 1 from dad - Mitochondria contains mitochondrial chromosomes Karyotype: graphic arrangement of chromosomes in a cell, arranged by size and position of centromere, numbered 1-22 / X and Y Autosomes: pairs of chromosomes that are the same in men and women (1-22) Sex chromosomes: different in men and women (X and Y) - Y contains genes that determine male sex, not much else - X contains a lot of genes in addition to sex (color blindness, hemophilia, muscular dystrophy) Homologs: pairs of the same chromosome - one maternal, one paternal, they are not identical Sister chromatids: duplicated copies of chromosomes, made after DNA replication and before cell division, joined at centromere, either maternal OR paternal, they are identical Alleles: variants of individual genes at a single genetic locus, two alleles for each gene Identify chromosome structure Chromatin: makes up chromosomes DNA + Histone = Nucleosome (Beads on a string), Nucleosome complexes form chromatin Associated with histone proteins = positively charged proteins that neutralize negative charge and allow DNA to compact itself Tightness of coiling controls gene expression Chromosomes Numbered in order of size (1 = largest, 22 = smallest, **exception: 21 is smaller than 22) Grouped by position of centromere: metacentric, submetacentric, acrocentric Centromere: divides chromosome into two parts (arms), attachment point for spindle fibers during cell division Arms: short arm (p), long arm (q) Banding: advanced staining techniques that reveal dark and light bands in chromosomes Dark bands = heterochromatin: more condensed, fewer expressed genes Light bands = euchromatin: less condensed, more expressed genes Chromosome nomenclature 1. Number of chromosomes (46 normal = 23 pairs) 2. Sex chromosome constitution (XX, XY, XXY, etc.) Numeric variance 1. Trisomy (extra chromosome): 21, 13, 18 – only trisomies seen at birth (others exist, however result in miscarriage) 2. Monosomy (missing chromosome): Turner syndrome – only non-lethal monosomy Structural variance 1. Translocations: piece of one chromosome attached to another a. Often reciprocal, balanced (pieces of chromosomes interchanged) b. Individuals with balanced translocations at risk for having children with unbalanced rearrangements (missing part of one chromosome, trisomic for piece of another chromosome) 2. Deletions: part of a chromosome missing, leads to monosomy of that portion a. Terminal: at end of chromosome b. Interstitial: in middle of chromosome c. Cause many syndromes (Prader-Willi, Angelman, Williams, DiGeorge) 3. Insertions: part of a chromosome is inserted or duplicated, leads to trisomy of that portion Explain the cell cycle including each phase of mitosis and meiosis  1. Interphase: resting phase a. G1 = cell metabolism and growth b. S = DNA synthesis and chromosome duplication c. G2 = cell metabolism and growth 2. Mitotic phase (M) = binary division of somatic cell a. Mitosis = division of chromosomes i. Prophase = chromosomes condense ii. Metaphase = chromosomes align along cell midline with spindle fibers, chromosome studies conducted during this stage (easy to visualize) iii. Anaphase = chromosomes split at centromere, chromatids drawn to each side of cell iv. Telophase = new cell membrane formed b. Cytokinesis = cell division Meiosis: happens in egg and sperm (in testes continuously after puberty, in ovaries before birth – held in stasis in meiosis I until fertilization) - Cells divide so only one copy of each homologous chromosome goes into each haploid gamete - DNA replication produces 92 sister chromatids 1. Meiosis I: cell becomes haploid via DNA replication a. Chromosome condensation i. 46 chromosomes made up of 92 chromatids b. Associate in homologous pairs (tetrads) c. Crossing over between arms of homologous chromosomes d. One homologous chromosome (2 chromatids) goes into each daughter cell  e. Two haploid daughter cells produced i. 46 chromatids but only 23 chromosomes technically 2. Meiosis II: similar to mitosis, no further DNA replication, daughter cells have 23 chromosomes – one of each homologous pair – four haploid daughter cells produced Define apoptosis Apoptosis = programmed cell death, produce apoptotic bodies which are cleared by phagocytes 1. Intrinsic pathway: cell suicide via internal signals (SMACs / MACs) **think intrinsic = internal 2. Extrinsic pathway: cell destruction via external activation (TNF) **thnk extrinsic = external Describe the function of the mitochondria and understand the impact/influence of mitochondrial dysfunction Mitochondria: subcellular organelles that contain respiratory chain and generate ATP Many other enzymes (Krebs cycle, urea cycle) Two membranes ○ Outer = permeable to small molecules ○ Inner = impermeable (except by specific transporters), contains bound enzymes Matrix = soluble enzymes Describe the mitochondrial genome Mitochondrial chromosome: circular, bacterial-like, replication start site, no introns Encodes some proteins (DNA replication enzymes, some respiratory chain components, set of tRNAs for protein synthesis) Come from ovum (maternal) *Most mitochondrial proteins / enzymes are encoded by nuclear genes and imported into mitochondria* Mitochondrial disorders: defects in respiratory chain activity, decreased ATP generation from oxidation (O2)  Symptoms: weakness / myopathy, neurologic symptoms, diabetes, blindness, hearing loss Some due to mutations in mitochondrial genome (show maternal pattern of inheritance) Many due to nuclear genome mutations Identify basic components and structure of nuclear DNA Components - Purine: adenine, guanine - Pyrimidine: thymine (unique b/c of extra methyl group), cytosine, uracil - Nucleotides: ribose, deoxyribose Amino groups of purines form hydrogen bonds with keto groups of pyrimidines Adenine - thymine (or uracil) Guanine - cytosine Structure Bases connected through ribose links (sugar-phosphate backbone) 5’ attached to 3’ via phosphate bridge (phosphodiester bonds) Directionality: 5’ → 3’ Describe the process of DNA replication, recognize the function of enzymes involved in DNA replication Simple Explanation Real Story Semiconservative replication Replication complex binds to origin of ○ One strand is the template, replication unchanged Helicase unwinds DNA to produce “bubble”, 2 ○ Second strand is newly synthesized replication forks DNA unwinds RNA primer synthesized to begin DNA synthesis A’s in DNA strand bind with free dTTP DNA polymerase extends primer 5’ → 3’ T’s in DNA strand bind with free dATP ○ Leading strand (3’ → 5’) G’s in DNA strand bind with free dCTP ○ Lagging strand (5’ → 3’) – small sections C’s in DNA strand bind with free dGTP called Okazaki fragments, connected by DNA polymerase creates new strand DNA ligase DNA repair / end correction Cytosine methylation is preserved Topoisomerase prevents unwinded DNA from tangling Telomerase extends telomeres (ends of chromosomes) with RNA template Describe the process and purpose of transcription Transcription = copying DNA sequence to produce mRNA for protein synthesis 1. RNA polymerase (3 types) binds promoter sequence upstream from gene, synthesize 5’ → 3’ a. TATA box - promoter sequence, specifies where transcription begins b. Uracil instead of thymine c. Binding regulated by enhancers and repressors Gene = linear stretch of DNA that codes for something Recognize the function of mRNA, tRNA, and rRNA Type of RNA Function Synthesized by mRNA Template for protein synthesis RNA polymerase II tRNA Binds amino acids with an anticodon, aligns amino acids for RNA polymerase III protein synthesis rRNA Provides RNA for ribosomes, important for binding of mRNA RNA polymerase I for protein synthesis Describe post-transcriptional modifications Capping PolyA tail Splicing = removal of intron sequences via spliceosomes (snRNA and proteins) - Loop out intron as RNA lariat - Alternative splicing can produce multiple proteins from one gene Describe the process and purpose of translation Translation = protein synthesis 1. mRNA exported to cytoplasm and binds to ribosomes 2. Start sequence: AUG (methionine) 3. tRNA with amino acid binds mRNA at A site 4. tRNA with amino acid added to polypeptide chain at P site  5. tRNA released from E site 6. Ribosome moves 3 bases in 3’ direction 7. Repeat until encounter stop codon Describe protein folding and modification Protein folding (occurs during synthesis, aided by chaperone proteins) - Ionic interactions between amino acids - Hydrophobic interactions - Disulfide bridges (covalent bonds between cysteine residues) Protein modification - Cleavage of pro-proteins to final product (e.g. insulin) - Association of multiple subunits (e.g. hemoglobin) - Addition of cofactors (e.g. heme) - Glycosylation of exported proteins in Golgi apparatus - usually end up in the blood Understand mechanisms of gene regulation - DNA methylation inhibits unwinding and RNA polymerase binding, turns genes off (part of epigenetics, don’t involve gene sequence but can still turn genes off) - Repressors / enhancers inhibit / activate binding to promoter sequences - Histone acetylation neutralizes positive charge of histone → more accessible for transcription - More histone acetylation → DNA more relaxed (see below) - mRNA regulation: splicing of introns, miRNA and RISC binding, mRNA stability (cap, polyA tail) - Protein folding and post-translational modifications Understand the various causes and different types of mutations Mutations = changes in DNA sequence that frequently occur in cell division, most are benign 1. Nucleotide level Single base changes May change single amino acid May not change anything – synonymous mutation Most common: C-T change at GC doublet ○ C in doublet may be methylated ○ Deamination changes C to T ○ During replication, T pairs with A instead of G ○ Cause of achondroplasia Single base insertions / deletions Within coding sequence = frameshift Codons after the mutation will be changed, early stop codon → severely defective protein  In frame insertions / deletions In multiple of 3, stay in frame → delete single / few amino acids → protein may be functional 2. Trinucleotide repeat expansion Some genes contain repetitive sequences of trinucleotides which can expand during meiosis If expansion is great enough, gene will not function properly and cause genetic disorder Examples ○ Huntington disease - CAG: glutamine repeat in coding region (paternal meiosis - children affected) ○ Fragile X - CGG near promotor (maternal meiosis - children affected) ○ Myotonic dystrophy - CTG in 3’ untranslated region (maternal meiosis - children affected) 3. Genome/chromosome level Copy number variants Genome contains many duplicated genes (beta-globin, alpha-globin, color vision locus) Genes may misalign during meiosis Crossover will delete gene on one chromosome, duplicate gene on the other X-linked color blindness (photo above): X-chromosome contains one red-sensitive pigment gene and several green sensitive ones (only first one is expressed) - Color pigment genes may misalign during meiosis I - Crossover can cause deletion of green sensitive gene or fusion with another color gene 4. Recurrent deletions Regions flanked by repetitive or inverted sequences Misalignment and crossover causes deletion in same places Describe the mechanism and function of DNA repair *DNA repair systems (3 below) cut out damaged bases or DNA segments, ligases repair DNA strand breaks* 1. Nucleotide excision repair a. Recognizes damaged bases that distort DNA helix (e.g. thymidine dimers caused by UV light) b. Damaged section cut out by endonuclease, removed by helicase c. New segment synthesized by DNA polymerase d. Reconnected by ligase 2. Base excision repair a. Single chemically damaged base cut out by glycosylase b. New base inserted by ligase 3. Mismatch repair a. Mismatched bases introduced during errors in DNA replication, recognized by repair system b. Segment cut out by endonuclease c. New strand synthesized by DNA polymerase d. Reconnected by ligase  MODES OF INHERITANCE Explain the principles of inheritance including segregation, independent assortment, autosomal dominant, autosomal recessive, and sex-linked inheritance Mendel’s Laws of Inheritance 1. Law of Segregation: separation of alleles (during meiosis) so each gamete only has one allele 2. Law of Independent Assortment: inheritance of one trait is independent of inheritance of other traits → inherited traits are a combination of parental traits 3. Law of Dominance: dominant allele will be expressed (homozygous dominant and heterozygous) unless there are two recessive alleles (homozygous recessive) Types of Inheritance Dominant inheritance: only one gene variant needed to cause problems (heterozygous “Rr”) ○ Can be caused by new mutation (1,700 variants at CFTR locus associated with cystic fibrosis Locus = variants at different genetic loci that cause the same phenotype ○ Ex. variants at 5 different genetic DNA repair genes associated with Hereditary Non-Popyposis Colon Cancer (Lynch Syndrome) Pleiotropy = variation of phenotypic effects of a single genetic variant (different phenotype results) Ex. variants at FBN1 locus → Marfan syndrome → affects skeletal system, eyes, heart, lungs Ex. cystic fibrosis - caused by pathologic variants at CFTR locus on chromosome 7 ○ i.e. some CFTR variants are more likely to cause pancreatic insufficiency than other variants, some cause male infertility, etc. Define mosaicism, homozygosity, heterozygosity, and hemizygosity Mosaicism = variation of genotype in different cells in the body, caused by post-fertilization events(mutations - single gene variants, nondisjunction - chromosomal variants) Homozygosity = both alleles at a locus have a variant Heterozygosity = one allele is normal (wild type), one is a pathological variant Hemizygosity = males with variants at a locus on X-chromosome Define lyonization, Barr body, XIST, and imprinting Lyonization = random permanent inactivation of X-chromosomes in females, process to balance X-linked gene expression in males and females (this process ensures that both males and females express the same number of genes from X chromosome) Barr body (photo to the right) = visualization of an inactive X-chromosome → condensed chromatin at the edge of nuclei Number of Barr bodies in a cell is one less than the number of X-chromosomes XIST (X-inactive specific transcript) = gene (found on X chromosome) responsible for X-chromosome inactivation → produces an RNA molecule that coats the inactive X chromosome → chromosome becomes silenced → compacted into Barr body **Reason only one X gets inactivated is bc once one chromosome expresses Xist, turns off signal that would cause same reaction in other chromosome → results in only one inactivated X chromosome**  Imprinting = epigenetic phenomenon resulting in differential expression of genes based on their parental origin via different DNA methylation patterns in maternal and paternal derived chromosomes Involves the marking or “imprinting” of genes during gamete formation (sperm or egg) in such a way that the expression of specific genes is influenced by whether they were inherited from mother or father Ex. Beckwith-Wiedemann syndrome, Angelman syndrome, Prader-Willi syndrome GENETIC COUNSELING *Genetic counseling is a communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family* Differentiate between screening, diagnostic, and predictive testing Definition Examples Screening Testing an entire population or group of Newborn screening (PKU, CF, sickle cell, population for pathologic genetic etc.) variants Carrier screening (Tay-Sachs, sickle cell, CF) Disease risk screening (cholesterol, cancer Unrelated to whether someone is genes) symptomatic Diagnostic Testing symptomatic individuals to find Cancer gene testing for those with early testing the cause of their disorder onset breast / colon cancer Muscle gene testing for children with Confirms diagnosis and can guide myopathy / cardiomyopathy treatment CFTR testing in individuals suspected of having cystic fibrosis Predictive Testing asymptomatic individuals to find Cholesterol levels to determine heart testing if they are at risk for l disease risk ater onset disorders Testing for cancer genes and Alzheimer’s disease risk genes Identify patients who would benefit from referral to a genetic counselor Prospective counseling: risks of transmission to future offspring Affected individuals with a genetic disorder / medical condition Individuals with positive family medical history Couples of “advanced” parental age Known carriers of autosomal recessive disorders Consanguineous couples (related to each other) Teratogen exposure (radiation, chemotherapy, medication) Individuals “at risk” for an adult-onset genetic disorder (predicted genetic testing) People who want screening disorders (even if not “at risk”) Retrospective counseling: evaluate / counsel individuals who may have a genetic condition (diagnosis, prognosis, treatment options) Affected individuals with a genetic disorder / medical condition Couples with a child with birth defects or potential genetic disorder Couples who have had >2 miscarriages / stillbirths Currently pregnant couples Counsel a patient on genetic screening and diagnostic testing options Requirements: accurate diagnosis, complete family history, determine pattern of inheritance, calculate genetic risk, explain diagnosis / risk to family, communicate with the family’s physician Describe the difference in information obtained from a chromosome test (karyotype) versus a comparative genomic hybridization Chromosome Test (Karyotype) Comparative Genomic Hybridization (Chromosomal Microarray) Requires living cells with nuclei Uses DNA segments attached to a silicon chip Cells cultured to cause division DNA from any source (does not need living cells, no culture or Chemicals added to hold them in division staining) Staining Machine reads the chip → analyzes chromosome number Analysis with a microscope → analyzes for missing pieces (deletions) or extra pieces Requires skilled technician (duplications) Examines chromosomes in a sample of cells to identify chromosome ○ Better resolution than standard chromosome study abnormalities as the cause of ○ Can find smaller changes (may be insignificant) malformation or disease Does not pick up balanced translocations Better at finding small deletions compared to karyotype (under a microscope) Explain the term ‘variant of uncertain significance’ Variant of uncertain significance = specific genetic alteration or mutation detected with genetic testing whose clinical implications / associations are uncertain or not well-established (further research is required) Discuss psychosocial aspects of genetic counseling including ethics, privacy, financing, and follow-up Emotional impact Decision-making Family dynamics Stigma / discrimination: employment, insurance coverage, personal relationships Ethical issues: informed consent, respecting autonomy, maintaining confidentiality, managing conflicts of interest Cultural / societal influences Psychological support Long-term psychological outcomes GENETIC DISEASES Types of Genetic Disorders (not on objectives) Chromosomal = abnormal number / structure of chromosomes (numeric, translocations, deletions, duplications)  Not “inherited” in the usual sense, can occur without prior family history Usually caused by de novo events (i.e. nondisjunction) Chromosomal analysis: standard karyotype, FISH test, chromosomal microarray Mendelian / Single locus Familial patterns of inheritance: autosomal dominant, autosomal recessive, X-linked, mitochondrial Due to variations at one gene locus, genes with major effects Inborn errors of metabolism, chondrodysplasias Complex / Multifactorial Conditions with genetic basis (i.e. diabetes, heart disease) Polygenic (multiple loci) Environmental influences Familial aggregation, rather than segregation ○ Single gene disease = segregate in definite pattern Largely determined by variant (mutation) in a single gene ○ Complex disease = cluster in families, but no clear pattern of inheritance Determined by several genes + environment Just because a trait aggregates in families does not indicate it is genetic (i.e family speaking French more likely to pass it on → however, NOT genetic) Traits influenced by genes in a complex way, not by simple mendelian genetics: height, IQ, blood cholesterol, MI, common birth defects (cleft lip / palate, club foot, cardiac malformations) Inheritance pattern of traits rather than single allele / gene Recognize the clinical features of the following chromosomal disorders Trisomy 21 (Down Syndrome) = extra copy of chromosome 21 Hall criteria (90% of DS children have 6 or more - not diagnostic on their own) Slanting palpebral features Single palmar crease (downward angle at inner corner of Small, dysplastic ears eyes) Incurved 5th finger (clinodactyly) Flat facial profile Low muscle tone (hypotonia) Loose skin at back of neck Decreased Moro reflex (Moro reflex = Hyperflexible joints baby spreads out arms, pulls arms back to chest, starts crying) Other features Flat nasal bridge Open mouth Epicanthal folds (at corners of eyes) Protruding tongue Gap between 1st / 2nd toes Brushfield spots (light colored spots Short, broad hands on iris) Associated problems Intellectual disability Duodenal atresia (causes vomiting) Cardiac malformations (contribute to neonatal mortality)  Hirschsprung disease (prevents Leukemia colon from contracting properly → (early) Alzheimer’s disease obstruction/constipation) Hypothyroidism Risk Overall 1/800 Increases with maternal age Decreased in-utero survival, increased spontaneous abortions (only 25% survive to birth) Recurrence risk ~1% – important to obtain a chromosome study on child Types of Trisomy 21 Three copies of long arm of Most common chromosome 21 (~95%) Robertsonian translocations (2-5%) 2 copies of chromosome 21 and 1 translocation of chromosome 21 at another chromosome location (14:21, 13:21, 15:21, etc.) Unrelated to maternal age Mosaicism (2-4%) Occurs after fertilization - nondisjunction Milder phenotype Recurrence risk for mosaic Down syndrome not increased Unbalanced translocations Partial trisomy 21 - have trisomy of part of 21 Trisomy of 21q22 causes heart defects, facial features, intellectual deficits Treatment Cardiac evaluation (even if Dietary counseling (weight asymptomatic) management, muscle tone) Thyroid hormone screening Educational intervention Hearing screening Family support Maternal Screening Tests (can also be used to detect trisomy 13 and 18) Triple screen / AFP (screening test, not diagnostic) - maternal serum ○ Low AFP → increased risk for Down syndrome ○ Triple/Quad screen more accurate ○ Screen for neural tube defects (i.e. spina bifida) High resolution ultrasound (not diagnostic) ○ Increased nuchal lucency ○ Measures amount of fluid behind baby’s neck in first trimester - too much fluid = possible indicator of DS NIPT - Non Invasive Prenatal Testing (screening test, not diagnostic) ○ Test of fetal DNA in maternal blood  ○ Chromosomal analysis - can detect trisomies Types of Chromosomal Disorders (not including trisomy 21 - see above) Prevalence Clinical features Treatment Trisomy 13 1/16000 Cleft lip, palate Considered lethal (Patau births Polydactyly (extra fingers, toes) If malformations Syndrome) Holoprosencephaly (cerebral hemispheres not are corrected, survival still limited completely separated) Severe disabilities Microphthalmia (small eyeballs) in survivors Skin defects on scalp Cardiac malformations Severe intellectual disability Trisomy 18 1/5000 IUGR (intrauterine growth retardation) (Edwards births Small, delicate appearance Syndrome) Hypotonia (decreased muscle tone) Overlapping of middle fingers Prominent occiput Cardiac malformations Severe intellectual disability Turner 1/2500 girls Occurs in females Evaluate all syndrome Short stature patients for cardiac (45, X) Only Infertility and renal non-lethal monosomy Early ovarian failure malformations, Congenital malformations regardless of ○ Ductus arteriosus → scar tissue can lead symptoms to coarctation of aorta (narrowing), Early referral to bicuspid aortic valve endocrinology ○ Cystic hygroma on back of neck (swelling) (treatment with ○ Horseshoe kidney growth hormone, Broad, webbed neck (cystic hygroma) estrogen / Broad chest (widely spaced nipples) progesterone) Lack of secondary sex characteristics (often Hearing testing don’t menstruate) Counseling (for Wide carrying angle of arms infertility) Normal intelligence May demonstrate X-linked genetic traits (i.e. X-linked color-blindness, Duchenne muscular dystrophy) Klinefelter 1/500 - Occurs in males - presence of two Testosterone Syndrome 1/1000 X-chromosomes replacement (47 , XXY) males Infertility  Lack of development of secondary sex Higher frequency of characteristics breast cancer Tall stature Evaluation for Gynecomastia (breast enlargement) infertility Small testes after puberty Family support, Low androgen (testosterone) production → not support groups, as much baldness, not as muscular genetic counseling Normal intelligence, may be in borderline range Fragile X 1/5000 Occurs in males - most common cause of Supportive males intellectual disability in boys Educational / Normal at birth behavioral Developmental delays (i.e. speech, ADHD) interventions Long face Observation for Prominent forehead seizure disorders Large jaw Genetic counseling Large ears Tall stature Lax joints Large testes All mothers of affected boys are carriers Recognize the clinical features of cancer predisposition syndromes Cancer results when cells escape normal cell mechanisms, evade apoptosis, divide rapidly, spread Cancer cells have genomic instability (mutations / chromosomal rearrangements) Cancer is heterogeneous Genetic cancer syndromes Defects in DNA repair → increased cancer risk ○ Often inherited as autosomal recessive traits ○ “Caretaker genes” ○ Xeroderma pigmentosa ○ Ataxia telangiectasia Other genetic cancer syndromes involve genes classified as ○ Tumor suppressor genes, proto oncogenes (see below) Proto-oncogenes Genes which promote cell proliferation and division (think “gas pedal”) Activated during embryonic development → generally inactivated in adult life Mutation that causes reactivation → stimulation of cell growth Can be activated by translocations which place gene near an active locus ○ i.e. Philadelphia chromosome translocation → results in CML Occurs post-fertilization, non-inherited translocation event Specific point mutations can cause them to escape their normal control  Tumor suppressor genes Inhibit cell growth → “gatekeeper” genes (think “brakes” on cell growth) Inactivating mutations in tumor suppressor genes allow cells to proliferate Generally, require inactivating mutations/deletions in both alleles ○ Think of the front and back brakes ○ Two hit hypothesis Two “hits” are necessary to inactivate both copies of tumor suppressor gene Two sporadic somatic mutations in the same cell One inherited mutation (genetic cancer syndrome), one sporadic mutation ○ Autosomal dominant inheritance pattern of increased susceptibility to cancer development Retinoblastoma BRCA1 Enabling mutations Telomerase activation ○ Lengthens ends of chromosomes, necessary for continued cell division p53 mutations ○ p53 controls apoptosis - most cancers contain mutations that inactivate p53 → increased ability to grow uncontrollably Genetic Cancer Syndromes BRCA1/BRCA2 Information Suggestive Findings Management Hereditary breast cancer Strong family history of breast Close observation syndromes / ovarian cancer Early intervention ○ Most breast ca is sporadic Age of onset < 50 Monthly breast self-evaluation - not associated with Bilateral disease Annual breast MRI starting BRCA1/BRCA2 variants Breast cancer in males at age 25 Autosomal dominant Prostate cancer Annual mammogram inheritance starting at age 30 Penetrance 50-80%, Consider bilateral depending on mutation prophylactic mastectomy / prophylactic oophorectomy BRCA1 only - information BRCA2 only - information 66% of hereditary breast cancer 33% of hereditary breast Tumor suppressor / DNA repair mutations (DNA breaks) cancer 80% risk of bilateral disease Tumor suppressor / DNA 40-60% risk of ovarian cancer repair mutations (DNA 8% risk of prostate cancer breaks) 60% risk of bilateral disease 25% risk of ovarian cancer 20% risk of prostate cancer 5% risk of male breast  cancer 5% risk of pancreatic cancer HNPCC Information Suggestive findings Treatment Hereditary non-polyposis Age of onset < 50 Colonoscopy every 1-2 colon cancer Multiple HNPCC related years after age 20 ○ Lynch syndrome cancers (colon, endometrial, Full colectomy after cancer Autosomal dominant gastric, ovarian) occurs Colon cancer risk 75% if High histologic instability Prophylactic hysterectomy carrier of gene High DNA instability in tumor and Family history salpingo-oophorectomy Multiple genes involved in DNA after childbearing mismatch repair FAP Information Suggestive findings Treatment Familial adenomatous > 10 colonic polyps Full colectomy once polyps polyposis Positive family history occurs ○ Gardner syndrome Connective tissue disorders Removal of osteoid tumors (connective tissue tumors) (desmoid tumors, osteoid Surveillance for liver, Autosomal dominant tumors) adrenal, thyroid cancer ○ Mutation in APC gene Hepatoblastoma (tumor suppressor) Colon covered with polyps after teenage years Colon cancer risk near 100% Increased liver cancer Identify different ways to manage and/or treat genetic disease Type Description Examples Supportive Family counseling, genetic counseling, social work Physical / occupational therapy Educational resources Treat manifestations (cardiac, renal, orthopedic) Product replacement Replace what is deficient Congenital adrenal hyperplasia (CAH) – replace therapy cortisol / aldosterone (supply missing small Hypothyroidism – replace thyroid hormone molecule) Biotinidase deficiency – biotin supplement Glycogen storage disorders – treat with glucose Enzyme replacement Replace enzyme in blood / lysosome therapy ○ Hemophilia, adenosine deaminase  Lysosomal enzymes ○ Gaucher, MPS Must get enzyme to proper location Cells need to be able to complete the rest of the pathway Dietary restriction Substance must be PKU – phenylalanine-restricted diet dietary dependent Urea cycle disorders – protein restriction Hypercholesterolemia – low fat diet Toxic substance Requires knowledge of Urea cycle disorders – nitrogen scavengers, removal pathophysiology benzoate / phenylacetate / phenylbutyrate Hemochromatosis (iron overload) – drawing blood Block synthesis of Requires knowledge of Hypercholesterolemia – statins, blocked toxic substance biochemistry, availability cholesterol synthesis of drug Tyrosinemia Type I – Orfadin, blocks tyrosine breakdown (blocks conversion of tyrosine to toxic metabolite) Gaucher disease – Zavesca blocks synthesis of glucocerebroside Transplantation Form of enzyme Bone marrow: sickle cell, SCID, lysosomal replacement, does not disorders treat involvement of other Liver: urea cycle disorders, tyrosinemia, glycogen organs storage disorders Gene therapy Experimental for most Ex-vivo therapy: cells removed, genes implanted disorders, very limited into those cells, cells grown to select for success so far for trans-gene, reimplanted non-bone marrow X-linked SCID disorders Hereditary blindness syndrome