Genetics and Cancer Biology

-ovum -spermatozoa

Somatic Cells

-all other cells -23 pairs of chromosomes -22 autosomes -1 pair of sex chromosomes

Germline Cells

-ovum -spermatozoa

Genes and DNA: Components

-nucleotides -histone proteins →gives structure to chromosomes

What are nucleotides made up of

-nitrogenous base -phosphate -sugar

Purines

-adenine -guanine

Pyridines

-Cytosine and thymine

Cell Division: Cell Cycle

G0→G1→S→G2→M

G1

preparing for replication/synthesis

S

Synthesis occurs -second strand of DNA put together

Cell Division: S Phase continued

1) DNA unwinds 2)DNA polymerase moves along the strand and creates a complementary strand based in the nucleotides on the template strand →proofreads the code and cuts if not accurate (CHECK AND BALANCES) → Two identical strands made

G2

-prepares for mitosis -gets spindle fibers together

Mitosis

-cell division

Cell Division: Mitosis: Prophase and Metaphase

Prophase: DNA shortening, copies being made Metaphase:chromosomes line up in the middle of the cell

Anaphase

spindle fibers attach to each chromosome → pulls to opposite sides of the cell

Telophase

-daughter cells are made -contain same genetic information -spindle fibers dissapear

Meiosis

-one copy of each chromosome -germline cells/gametes

Meiosis I

-2 copies of chromosomes from each parent

Meisosis

Prophase I→ Metaphase I →Anaphase I (homologous chromosomes are pulled apart)→Telophase I =two daughter cells (DIPLOID)

Metaphase II

Copied chromosomes line up

Anaphase II

pull apart of the chromosomes again

Telophase II

1 Copy of Each chromosomes (Haploid)

Mutations":Polyploidy

-multiple chromosomes -triploidy, tetraploidy -spontaneous abortion

Mutation: Aneuoploidy

-does not have multiple of 23 chrosomes -trisomy(down syndrome) -Monosomer

Nondisjunction

uneven splitting of chromosomes (either during meiosis 1 or 2)

Trisomy 21 (Down Syndrome)

-low IQ -epicanthal fold -missing nosebridge -short stature -pointed down ears -cogential heart defects -Alzheimers by 40

Turner Syndrome (45,X)

-X Chromosome without an X or Y -AFAB -webbing neck -sparse body hair

Klinefelter syndrome (47, XXY)

-Two or more X chromosomes in addition to Y -AMAB -gynecomastia -sparse body hair -infertility

Abnormalities associated with chromosome structure

-deleton (one genetic code missing) -duplication(redundant) -Inversion: reversal of code Translocation: interchanging of 2 non-homologous chromosomes

Cri du chat

-deleton of short arm of chromosome 5-high-pitched cry -wide set eyes and epicanthol fold -intellectual disability

Fragile X Syndrome

-repeat of 3-nucleotide sequence in long arm of X chromosome -leads to silencing of genes -enlarged genitalia, elongated face -mood disturbances -sensory and motor deficits

Proteins

-made up of a sequence of amino acids that can create a polypeptide -ex:albumin common protein in out blood

Protein Synthesis

DNA→RNA→Protein

Protein Sysnthesis:Transcription

-RNA polymerase unwinds DNA and binds to promoter site → A-U and G-C→ Termination end → mRNA is made

Protein Synthesis: Removal of introns

-Snip out intorns —> mechanism is unknown

Protein Synthesis: Translation

Identification of codon →tRNA is called in and has ANTICODON(three codons that match) and an amino acid → more tRNA bind to adjacent codons and create a polypeptide from each amino acid it brings

Genetics and Transmission of Genetic Disease: Dominant and Recessive

Domimant: BB,stronger expression Recessive : bb, weaker expression

Phenotype

-refers to observable trait (eye color, hair color, etc)

Genotype

-genetic makeup -homozygous dominant, homozygous recessive, or heterozygous dominant

Genetics and Transmission of Genetic Disease: Disease Carriers

-carrier of a disease, however phenotypically normal. -the disease allele is recessive

In order to express disease →

-Both recessive alleles have to be present (e.g: Tay-Sachs, Sickle-cell, Cystic Fibrosis)

Cystic Fibrosis

autosomal recessive -mutation in the ion channel (leads to obstructions) -build up of mucous in airways pancreas duct, vas deferens, sweat glands(salty sweat)

Cystic Fibrosis: Clinical manifestation

Mucus accumulation in the lungs due to abnormal ion channels →increase mucin production in GI tract/pancreatic ducts/digestive enzymes aren’t made → increase in NA+ and Cl- in sweat due to poor absorption

Huntington Disease (Huntingtons Chorea)

-autosomal dominant (1 copy leads to expression of disease) -onset at 45 -abnormal neuronal function -motor dysfunction -bradykinesia -death occurs 10-30 years after onset

Incidence and Prevalence:Men

Prostate, Lung/Bronchus, colon/Rectum

Incidence and Prevalence:Women

-Breast -Lung/bronchus -colon/rectum

Prevalent Cancer in Both

Lung/Bronchus due to late detection

Etiology of Cancer

-occurs via mutation or epigenetic mechanisms -pint mutations -translocation -repetitions

Etiology of Cancer: Oncogene

-mutations of proto-oncogens → extensive cellular growth and development -e.g., RAS and HER-2

Etiology of Cancer: Tumor Supression genes

-mutation prevents activation of these genes→ allows cell division to grow, leading to cancer growth

Etiology of Cancer: Tumor Suppression Genes Examples

BRCA-1 BRCA-2 defect(important for breast and ovarian cancer) and APCE gene mutation

Influence of Genetic Changes

-Proliferation -Differentiation (cells become specialized) -Maturity

Proliferation

cell division

Differentiation

-cells become specialized -regulated by genes and external stimuli (cytokines, growth factors)

Maturity

Differentiated cells have reached their full potential

Stem Cells properties

-self-renewal (divides however one remains its original stem cell) -potency (cadiac cell, pancreatic cell, any cell it wants)

Cancer Cell characteristics

-abnormal and rapid replication -anaplasia(loss of differentiation) -immature/stem cell-like -nuclei are in odd chape usually Garde IV differentiated (poor)

Cancer Cell Characteristics 2

-genetic instability -growth factor independence -continues division in spite of crowdiness

Cancer Cell Characteristics 3

-loss of adhesion/loss of anchorage dependence -loss of cell-cell communication

Cancer Cell Characteristics 4

-antigen expression -production of enzymes, hormones (e.g. lung cancer producing ACTH) → leads to paraneoplastic syndromes -cytoskeletal changes -” unlimited life span” - cancer produces telomerase, which prevents telomere shortening

Neoplasma Nomenclature

-benign tumors = -oma ending (Osteoma) -malignant tumors = -carcimona ending Malignant neoplasm of mesenchymal origin= -sarcoma ending (liposarcoma)

Categories of malignant neoplasms

-solid tumors -hematologic cancers -carcinoma in situ

Molecular/Cellular Pathways that
Promote Cancer Growth and Survival 1

-DNA repair defects -Defects in growth Factor Signaling pathway- Evade apoptosis _evades cellular senescence (telomerase production→prevents chromosome unraveling) -develop their own blood supply (angiogenesis via VEGF)

Molecular/Cellular Pathways that
Promote Cancer Growth and Survival 2

-Evade apoptosis -Evades cellular senescence (telomerase production→prevents chromosome unraveling)

Molecular/Cellular Pathways that
Promote Cancer Growth and Survival 3

-develop their own blood supply (angiogenesis via VEGF) -invasion and metastais

Host Factors that Promote
Cancer Growth and Survival 1

-Hormones -hereditary

Host Factors that Promote
Cancer Growth and Survival 2

-Cancer leads to impaired ability to suppress tumor growth

Example of Tumor Cells

NK cells and cytotoxic T cells

Environmental Factors That Promote Cancer

-Chemical Carcinogens -Radiation -Bacteria -Viruses

Environmental Factors of Cancer: Chemical Carcinogens

-smoking -diet -alcohol

Environmental Factors of Cancer: Radiation

-Iodizing(X-Rays) -Non Iodizing (UVA)

Environmental Factors of Cancer: Bacteria

Helicobacter pylori

Environmental Factors of Cancer:Viruses

HPV(Human Papillomavirus), EBV (Epstein-Barr), HBV

Clinical Manifestations of Cancer 1

-fluid buildup/edema -tumors compress vessels→bleeding or hemorrhage -tumors produce enzymes that destroy tissues

Clinical Manifestations of Cancer 2

-Anorexia-cachexia syndrome(energy imbalance, hypermetabolic state) -fatigue (multifactorial)

Clinical Manifestations of Cancer 3: Anemia Factors

-hemolysis -chemotherapy -inflammatory cytokines -bone marrow failure -nutritional deficiency

Clinical Manifestations of Cancer 4

-GI disturbances -Alopecia (chemotherapy) -Lymphedema (fluid in tissue) -Pain

Clinical Manifestations of Cancer 4:Paraneoplastic Syndrome

-Paraneoplastic syndrome → symptoms that occur indirectly from primary cancer cells

Clinical Manifestations of Cancer 4: ACTH secretion

tumor secretes ACTH→ too much cortisol released → hyperglycemia, HTN Cushing Syndrome

Clinical Manifestations of Cancer 4: ACTH secretion

tumor secrets ADH→ water retention →hyponatremia → headaches, confusion, weakness

Clinical Manifestations of Cancer 4: PTHRP

tumor secrets PTHRP→ hypercalcium due to calcium taken from bones →weakness, constipation, kidney stones

Clinical Manifestations of Cancer 4: Erythropoietin

-Tumor secretes excess erythropoietin→polycythemia (too many RBCs) →HTN, headaches

Screening and Diagnosis of Cancer:
Secondary prevention

-secondary prevention e.g: pap smear, colonoscopy, mammography