Genetics & Cancer Lecture Notes

GENETICS & CANCER

Kaveri Roy, DNP, RN, CNE

ANNOUNCEMENTS

• Instructor available to answer questions post-class.
• Regularly check the “Announcements” on D2L.
• Topics to review:
    - Race and genetics
    - Case Study
      - Know your group number
      - One person per group submits the assignment
      - Use Google Docs or Teams for collaboration
    - Proper pronoun usage is mandatory.
    - Accepted resources: Porth, Lewis, reputable websites.
    - All sources for each question must be cited; PowerPoint slides cannot be cited.
    - APA citation format is required.

ATTENDANCE

Attendance details were likely covered, but are not specified in the transcript.

LECTURE MAP

• Overview of related topics:
    1. Genetic/congenital disorders
       - Marfan syndrome
       - Neurofibromatosis
       - Phenylketonuria
       - Tay-Sachs Disease
    2. Multifactorial inheritance disorders
       - Cleft lip and palate
    3. Aneuploidy disorders
       - Turner syndrome
       - Klinefelter syndrome
       - Down syndrome
    4. Environmental factors
    5. Cancer
       - Malignant vs. benign tumors
       - Oncogenesis
       - Metastasis
       - Diagnosis and classification of cancer
       - Cancer manifestations
       - Cancer treatments

GENETIC/CONGENITAL DISORDERS

• Presented data:
  $15,000$ genetic code segments were mentioned with a sequence:
  $GJAG, TAGO, ACA, TGH, AGG, TCTCTTCAGCC) CACT T GAC$
  

REVIEW – ALLELES

• Chromosomes:
    - Autosomal chromosomes: 22 pairs (diploid)
    - Sex-linked chromosomes: 1 Pair (XX or XY)
• Genetic basics:
    - Chromosomes are paired.
    - Gene locus: Position of a gene on a chromosome.
    - Alleles: Two copies of a gene at the same locus.
       - Homozygous: Trait with two alike alleles.
       - Recessive trait: Expressed only in homozygotes.
       - Heterozygous: Trait with differing alleles, expressed if dominant.
• Carriers: Individuals heterozygous for a recessive trait who do not express it.
• Incomplete penetrance: Phenomena where not all individuals with a genotype express the expected phenotype.
• Example: Eye color alleles - $Bb$ (b = brown, B = blue).

REVIEW – PUNNETT SQUARES

• Definition:
    - Punnett Square is a diagram to show gene combinations resulting from genetic crosses.
• Purpose: Calculate the probability of inheriting specific traits.
• Probability: The likelihood that a certain event occurs.

REVIEW - PUNNETT SQUARES

• Illustration of probability of sex-linked trait inheritance:
  
  $X imes X$
  
    Produces combinations:
  $XX, XX, Y, XY, XY$

MARFAN SYNDROME

• Overview:
    - Type: Autosomal Dominant (75% familial)
    - Genetic basis: Mostly a genetic disorder linked to chromosome 15, can arise from spontaneous mutations.
    - Affects: The gene that controls fibrillin-1 production, which is vital for microfibril formation [connective tissue].
    - Incidence: 1 in 20,000 individuals.
  

Systems Involved:

• Skeletal: Abnormally long body structure
• Ocular: Vision problems
• Cardiovascular: Serious heart conditions.

MARFAN SYNDROME

• Clinical Manifestations:
    - Physical characteristics:
      - Long, thin body structure, exceptionally long extremities, arachnodactyly (long fingers), hyperextensible joints, and varying chest deformities including pectus excavatum (concave) or pectus carinatum (protruding).
    - Other skeletal deformities include kyphosis (hunchback) and scoliosis (curved spine).
    - Visual: Issues such as lens dislocation (ectopia lentis) and myopia (nearsightedness).
    - Cardiac issues: Love related conditions include mitral valve prolapse, aortic aneurysm, and risk of aortic dissection, leading to potential sudden death.

MARFAN SYNDROME

• Visual References:
    - Conditions shown: Pectus excavatum and pectus carinatum.

NEUROFIBROMATOSIS

• Overview:
    - Originates from neurogenic tumors, arises from nerve cells.
    - Incidence: 1 in 3,000 individuals associated with chromosome 17, with 50% of cases being autosomal dominant and 50% arising from mutations.
    - Types:
      - NF1 (Recklinghausen disease, more prevalent).
      - NF2 (Bilateral Acoustic NF).
• Symptoms:
    - Headaches, hearing loss, tinnitus, disorientation; neurological issues such as ADD, learning disabilities, speech difficulties, and seizures.
    - Indicators:
      - Lisch nodules (pigmented iris lumps), café au lait spots (large brown pigmented areas with sharp edges on skin, 6 spots >1.5 cm).

NEUROFIBROMATOSIS

• Tumors:
    - Diverse types of neural tumors throughout the body; soft, pedunculated lesions under the skin, potentially painful.
    - Differentiation between cutaneous and plexiform neurofibromas, with the latter leading to severe disfigurement, bone fractures, and chest wall abnormalities.
    - Risk of pheochromocytomas leading to hypertension, and epilepsy.
    - Social implications: frequent discrimination, anxiety, depression.
  

Care:

• Requires interdisciplinary care approaches during childhood/adolescence.

PHENYLKETONURIA (PKU)

• Category: Autosomal recessive disorder with an incidence of 1 in 12,000 individuals found equally in males and females, associated with chromosome 12.
• Pathophysiology: Metabolic disorder with elevated phenylalanine levels toxic to the brain due to deficiency of phenylalanine hydroxylase, leading to its accumulation.
  

Clinical Features:

• Unpleasant body odor in sweat and urine, lighter skin and hair color due to tyrosine imbalance.
• Intellectual impairment, microcephaly and low birth weight in pregnancies with PKU mothers, seizures, and eczema.
• Management:
    - Newborns are routinely screened; treatment involves a low-protein diet avoiding meat, dairy, eggs, nuts, and beans (Phenyl-Free).
    - Medications like Pegvaliase (risk of anaphylaxis) and Saproterin (not universally effective).

TAY-SACHS DISEASE

• Genetic Basis: Autosomal recessive disorder linked to chromosome 15, with a higher prevalence in Ashkenazi Jewish populations (1 in 30).
• Mechanism: Lipid accumulation within CNS lysosomes due to failure of lysosomes to degrade GM2 ganglioside caused by deficiency of beta-hexosaminidase A.
• Symptoms: Infants appear normal at birth but progress to weakness and muscle flaccidity (6-10 months), leading to deterioration of motor and mental functions, seizures, blindness, and hearing loss.
• Outcomes: Death typically occurs around ages 4-5; genetic testing and interventions include possibility of bone marrow and stem cell transplants.

MULTIFACTORIAL INHERITANCE DISORDERS

• Definition: Disorders influenced by multiple genes and environmental factors including Socio-Demographic-Determinants of Health (SDOH).
• Examples of congenital disorders:
    - Cleft lip/palate, clubfoot, congenital heart diseases.
• Disorders appearing later in life: Environmental factors influence disorders like coronary heart disease, cancer, diabetes, hypertension, and mental health issues.
• Recurrence Risk: Increases with family incidence and severity of initial defects (3-5%).

MULTIFACTORIAL INHERITANCE DISORDERS - CLEFT LIP AND CLEFT PALATE

• Prevalence: Common birth defect, particularly among East/South Asian populations and Indigenous Peoples at a rate of 2 in 1000 births. Disruptions may occur due to medications or infections like rubella during early pregnancy.
• Pathophysiology: Failure of normal craniofacial and maxillary fusion process around Day 35.
• Manifestations: Issues with teeth development, fleet alternatives like feeding and speech difficulties, and susceptibility to ear infections and hearing loss.
• Intervention: Multiple surgeries, special feeding bottles, and obturators (artificial palates) are often used (e.g., Operation Smile).

ANEUPLOIDY

• Definition: Conditions resulting from loss or gain of chromosome(s), can manifest as monosomy or polysomy.
• Major Conditions:
    - Turner syndrome (monosomy): Missing all/part of X chromosome (X0), incidence of 1 in 2000, typically female at birth.
    - Klinefelter syndrome (polysomy): Extra X chromosome (XXY), incidence of 1 in 500, often male assigned at birth and showing significantly higher rates of developmental deficits.
    - Down syndrome (Trisomy 21): Incidence correlates with maternal age, with a risk of 1 in 25 at age 45, assessment through prenatal screenings.

ANEUPLOIDY - TURNER SYNDROME

• Clinical Features:
    - Small stature, webbed neck, broad chest with wide-spaced nipples, poor breast development, and ovarian dysgenesis leading to primary amenorrhea.
    - Associated anomalies include aortic coarctation, pigmented nevi, lymphedema of hands and feet, and retarded bone age.

ANEUPLOIDY - KLINEFELTER SYNDROME

• Overview:
    - Present as XXY genotype; male characteristics are altered with features such as gynecomastia (breast tissue enlargement), narrow shoulders, and long limbs.
    - Additional manifestations include reduced facial and pubic hair, testicular atrophy, and infertility.

ANEUPLOIDY - DOWN SYNDROME

• Clinical Manifestations:
    - Characterized by distinct facial traits (epicanthic folds, flat facial profile), congenital heart disease, growth failure, and a high likelihood of presenting with Alzheimer's-like symptoms later in life.
    - Common juvenile cancers include acute lymphoblastic leukemia.

ENVIRONMENTAL FACTORS - TERATOGENIC AGENTS

• Definition: External environmental influences impacting embryo development during organogenesis (Day 15 - Day 60 post conception).
• Examples:
    - Radiation exposure (e.g., X-rays) associated with microcephaly and skeletal malformations.
    - Chemical exposures (e.g., Vitamin A overdose leading to cleft palate and heart defects).
    - Infectious agents (e.g., Rubella, Toxoplasmosis).

ENVIRONMENTAL FACTORS - FETAL ALCOHOL SYNDROME

• Incidence: Affects 1 in 20 (5%) pregnancies in the US.
• Mechanism: Alcohol crosses the placental barrier freely affecting fetal growth and neurological development.
• Clinical Features:
    - Growth deficits, neurologic delays, microcephaly, and peculiar facial characteristics (small palpebral fissures, smooth philtrum).

CANCER

• Presentation:
    - Described as a malignant cell emerging from a tissue (epithelium), leading to systemic implications.

LGBTQIA+ CONSIDERATIONS

• Increased prevalence and risk profiles:
    - Men who have Sex with Men (MSM) show higher risks for prostate, testicular, and colorectal cancers, linked to lifestyle factors and lower screening rates.
    - Trans-female and trans-male populations exhibit increased incidence in breast and gynecological cancers due to hormone therapy impacts and access to care disparities.

CELL GROWTH

• Components influencing cell growth:
    - Number of actively dividing cells, duration of the cell cycle, comparison between number of cells lost and produced, ratio of dividing cells to resting cells.

ALTERED CELL GROWTH

• Definitions:
    - Atrophy: Reduction in cell size or number.
    - Hypertrophy: Increase in cell size.
    - Hyperplasia: Increased cell number (normal cells).
    - Metaplasia: Change of one cell type to another.
    - Dysplasia: Abnormal changes in cell appearance and function.
    - Anaplasia: Loss of cell differentiation and structure.
    - Neoplasia: Abnormal cell proliferation rates.

BENIGN VS MALIGNANT TUMORS

• Key Differences:
    - Benign Tumors: Well organized, encapsulated, normal cell structure, typically non-invasive, slow-growing localized.
    - Malignant Tumors: Rapid growth, disorganized structure, often invasive and capable of metastasizing.

MALIGNANT TISSUE/CELLS

• Characteristics:
    - Transformed cells that do not require growth factors for propagation, lack contact inhibition, can survive and proliferate without anchorage, and often show impairments in cell-to-cell communication.

CANCER ASSOCIATED GENES

• Proto-oncogenes:
    - Code for proteins essential for normal cell division, but mutations transform them into oncogenes, leading to increased cell division.
    - Tumor suppressor genes function to inhibit unregulated cell growth; mutations can decrease their functional capability causing unchecked proliferation and viability of mutant cells.

ONCOGENESIS

• Definition: Prerequisite accumulation of mutations within DNA, often involving proto-oncogenes and tumor suppressor genes leading to heightened cell divisions and tumor formation.

STAGES OF ONCOGENESIS

• Phases:
    - Initiation: Initial mutation, often induced by carcinogens; deemed irreversible.
    - Promotion: Stimulated growth of mutated cells; can be reversible.
    - Progression: Further mutations become more aggressive, leading to invasive behavior and metastasis.
  

Mechanisms of Spread:

• Direct invasion, seeding in body cavities, lymphatic, and hematogenous spread.

METASTASIS

• Process: Cancer cells detach from the original tissue and facilitate new tumor formation at distant sites.
• Lymphatic Spread: Involves lymph node pathways (first node/sentinel node).
• Blood Vessel Spread: Characterized by a loss of cellular adhesion and enzymatic degradation of extracellular matrices, allowing entry into circulation.

HOST & ENVIRONMENTAL FACTORS

• Contributing Factors:
    - Aging, chronic inflammation, and obesity.
    - Hormonal influence related to breast/endometrial cancer and prostate cancer.
    - Genetic predispositions, such as BRCA1 and BRCA2 mutations, immune deficiencies, viral/bacterial influences (e.g., HPV, EBV, Hepatitis).
    - Chemical carcinogens (e.g., cigarettes, asbestos) and radiation exposure.

HOST & ENVIRONMENTAL FACTORS - CLIMATE CHANGE

• Impact of Climate Change on Cancer Risk:
    - Increased carcinogenic agents due to worse air quality, rising temperatures, and extreme weather conditions influence cancer risk and access to healthcare.

HOST & ENVIRONMENTAL FACTORS - VIRAL AND BACTERIAL INFLUENCES

• Major Viral Risks:
    - Hepatitis B/C, HPV strains 16, 18, 31, 33, 45, 52, and 58 are significantly linked to tumors, especially cervical and hepatocellular cancers.
• Bacterial Factors:
    - H. pylori linked to peptic ulcer disease and several types of stomach cancers.

CANCER DIAGNOSIS

• Methods:
    - Tumor markers, cytologic studies (e.g., Pap smears), tissue biopsies, and immunohistochemistry to identify tumor type and origin.
    - Advancements in microarray technology facilitate understanding cancer gene expression and therapy responses.

TUMOR MARKERS

• Definition: Substances produced by cancer cells, detectable in bodily fluids, used for screening, diagnosis, and patient monitoring.
• Notable Tumor Markers:
    - Oncofetal antigens like alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA)
    - Hormones (e.g., human chorionic gonadotropin (hCG), calcitonin)
    - Specific proteins (e.g., prostate-specific antigen (PSA), abnormal immunoglobulin)
    - Glycoproteins (e.g., CA-125, CA-19-9) important for various cancer types.

CLASSIFICATION: GRADING VS STAGING

• Grading: Classifies tumors based on microscopic differentiation levels from grade I (well differentiated) to IV (poorly differentiated).
• Staging: Evaluates the extent and dissemination of cancer to guide treatment plans and prognosis.
    - Example Stages: Stage I (localized), Stage II (locally invasive), Stage III (regional spread), Stage IV (distant metastasis).

TNM SYSTEM

• Components:
    - T (Tumor Size): Ranges from 1 to 4.
    - N (Node Involvement): Ranges from 0 to 3.
    - M (Metastasis): 0 (no distant metastasis) or 1 (with distant metastasis).
  

Interpretation Example:

• A classification of T4N3M1 specifies extensive tumor involvement with regional lymph node metastasis and distant spread.

LOCAL EFFECTS OF TUMOR GROWTH

• Clinical Consequences:
    - Inflammation, obstruction of adjacent structures, vascular compression leading to hematological issues, and effusions (e.g., pleural, ascites).

SYSTEMIC EFFECTS OF CANCER

• Associations:
    - Anemia due to bone marrow failure.
    - Anorexia and cachexia due to cytokine-induced alterations affecting metabolism and satiety.
    - Fatigue and its systemic impact on patient quality of life.

PARANEOPLASTIC SYNDROMES

• Nature: Unique effects stemming from cancerous cells producing hormones or hormone-like proteins causing symptoms beyond the original site (e.g., hypercalcemia via PTH-like substances).
• Remarks: Impact on coagulation leading to increased thrombotic events and related complications.

OTHER SYMPTOMS OF CANCER

• Symptoms may include: Pain, immunosuppression, infections, gastrointestinal disturbances (e.g., nausea, vomiting), and psychological effects like anxiety and depression.

CANCER TREATMENT

• Key Approaches:
    - Surgery for tumor removal and/or symptomatic relief.
    - Radiation therapy to target cancer cells, potentially increasing efficacy through combination with chemotherapy and interventional therapies.

CANCER SURGERY

• Focus: Surgical intervention involves the excision of tumor tissues when feasible.
• Goals: May include definitive cure, staging, or palliation of advanced disease, often in union with adjuvant therapies.

RADIATION THERAPY

• Purpose: Selected treatment for specific tumors to mitigate growth and relieve discomfort.
  

Mechanism:**

• Ionizing radiation (e.g., gamma rays, brachytherapy) effectively kills rapidly dividing cells while attempting to spare normal cells.

RADIATION THERAPY - SIDE EFFECTS

• Localized Effects:
    - Mucositis leading to pain and reduced salivary function, potential for GI disturbances (e.g., nausea, diarrhea).
    - Skin reactions leading to burns (dry or wet desquamation).
• Systemic Effects:
    - Generalized fatigue and hematological complications like anemia and leukopenia.

CHEMOTHERAPY

• Definition: A therapeutic application of cytotoxic drugs to curb cancer cell proliferation and development through cessation of cellular replication.
• Context: Often applied as an adjunct post-surgery/radiation to eliminate residual malignancy.

CHEMOTHERAPY - MECHANISM

• Cell-Kill Hypothesis: Multiple cycles of chemotherapy kill a percentage of tumor cells but ultimately leave some alive, requiring ongoing treatment until sufficient clearance is achieved for immune system recovery.

CHEMOTHERAPY - GENERAL NOTES

• Application: Involves systemic administration impacting metastasis even beyond the primary tumor site; typically utilizes multifaceted drug regimens for enhanced efficacy.

CHEMOTHERAPY - SIDE EFFECTS

• Short-term Effects: Immediate nausea/vomiting due to chemoreceptor stimulation.
• Common Complications: Mucositis, bone marrow suppression inducing anemia and leukopenia, fatigue, diarrhea, and hair loss.

HORMONE/ANTIHORMONE THERAPY

• Mechanism: Hormonal intervention aims to block hormone-dependent cancer cell division (e.g., Tamoxifen for breast cancer). This is applicable to malignancies of the breast, prostate, ovary, and endometrium.

IMMUNOTHERAPY/TARGETED THERAPY

• Introduction: Utilizes monoclonal antibodies and biological response modifiers (e.g., interleukins, interferons) aimed at enhancing immune responses against tumor-specific antigens.

QUESTIONS