Dr. Irungu Notes — Notes OmpathStudy

15 SHORT ANSWER QUESTIONS (5+ marks) Q1. Describe the hallmarks of cancer. Self-sufficiency in growth signals — RAS locked GTP-active, HER2 overexpression Insensitivity to growth inhibitors — RB loss, TGF-β pathway loss Evasion of apoptosis — BCL-2↑ blocks cytochrome c; p53 loss removes damage trigger Limitless replicative potential — telomerase reactivation bypasses senescence Sustained angiogenesis — HIF-1α stabilized by hypoxia → VEGF Invasion/metastasis — E-cadherin loss, MMP-driven ECM degradation Immune evasion — PD-L1 upregulation inhibits cytotoxic T cells (Emerging) Reprogrammed metabolism — Warburg effect, MYC-driven glycolysis Conclusion: cumulative, stepwise acquisition of these — not one mutation Q2. Compare oncogenes and tumour suppressor genes. Oncogenes: from proto-oncogenes, gain-of-function, only 1 allele needed (dominant), activating mutation — examples: RAS, HER2, BCR-ABL, MYC Tumour suppressors: loss-of-function, both alleles needed (Knudson two-hit), recessive at cell level — examples: RB, p53, APC, BRCA1/2 Key line: oncogene mutations = activating; TSG mutations = inactivating Q3. Explain Knudson's two-hit hypothesis using retinoblastoma. Both RB alleles must be inactivated for retinoblastoma Hereditary: 1st hit germline (present in every cell) → only 1 somatic hit needed → early + bilateral Sporadic: both hits must occur in same cell by chance → later + unilateral Explains classic clinical pattern; same logic applies to BRCA1/2, APC Q4. Describe the intrinsic apoptosis pathway and how BCL-2 disrupts it. DNA damage/stress activates BAX/BAK BAX/BAK form pores in outer mitochondrial membrane Cytochrome c released into cytosol Cytochrome c + APAF-1 → apoptosome → caspase-9 → caspase-3 → apoptosis BCL-2 blocks BAX/BAK → prevents pore formation/cytochrome c release Clinical: follicular lymphoma t(14;18) → BCL-2 overexpression → apoptosis resistance Q5. Outline the steps of tumour invasion and metastasis. 1. Detachment — loss of E-cadherin 2. ECM degradation — MMPs, cathepsins 3. Migration — altered integrins, cytoskeletal remodeling 4. Intravasation — entry into blood/lymphatics 5. Survival in circulation — evade anoikis, immune surveillance (PD-L1) 6. Extravasation — exit vessel at distant site 7. Colonization — proliferation + new angiogenesis (VEGF) Q6. Differentiate the major patterns of inheritance with examples. AD: 1 allele sufficient, vertical transmission, every generation, 50% risk — Huntington, Marfan AR: both alleles needed, carrier parents unaffected, skips generations, 25% recurrence — CF, PKU X-linked recessive: mostly males affected, carrier mothers, no male-to-male transmission — DMD, Fragile X Mitochondrial: maternal transmission to ALL children, fathers transmit none, variable severity (heteroplasmy) — LHON Q7. Explain genomic imprinting and contrast Prader-Willi with Angelman syndrome. Imprinting = gene expressed from only one parental allele, other silenced by methylation Same locus: 15q11–13 Paternal deletion → Prader-Willi — hypotonia, hyperphagia/obesity, intellectual disability, hypogonadism Maternal deletion → Angelman — severe intellectual disability, ataxia, seizures, inappropriate laughter Teaching point: same region, opposite parent-of-origin, opposite disease Q8. Describe the karyotype and clinical features of Turner, Klinefelter, Down, and Edwards syndromes. Turner (45,X): short stature, webbed neck, streak ovaries, coarctation of aorta, primary amenorrhea Klinefelter (47,XXY): tall, gynecomastia, small testes, infertile, ↓testosterone ↑LH/FSH Down (Trisomy 21): simian crease, AV septal defect, ↑leukemia risk, hypotonia, early Alzheimer's Edwards (Trisomy 18): micrognathia, clenched fists, CHD, rocker-bottom feet, poor prognosis (Patau, Trisomy 13, if asked): cleft lip/palate, holoprosencephaly, polydactyly, CHD, poor prognosis Q9. Differentiate endometriosis from adenomyosis. Endometriosis: glands/stroma OUTSIDE uterus (ovary, peritoneum) → chocolate cysts, cyclic pelvic pain, infertility, "powder-burn" lesions on laparoscopy Adenomyosis: glands/stroma WITHIN the myometrium → diffusely enlarged boggy uterus, dysmenorrhea + menorrhagia, typically multiparous women 40s Key distinguishing point: location of ectopic tissue determines the different clinical pattern Q10. Outline the grades of endometrial hyperplasia and their malignant potential. Cause: unopposed oestrogen (no balancing progesterone) — risk factors: obesity, PCOS, nulliparity, early menarche/late menopause, oestrogen-only HRT Simple hyperplasia without atypia — mild crowding, low risk Complex hyperplasia without atypia — glandular crowding/complexity, still low-moderate risk Hyperplasia WITH atypia — nuclear atypia, highest risk, direct precursor to endometrial carcinoma Progression: unopposed oestrogen → hyperplasia → atypia → carcinoma Q11. Match the major causes of vaginal discharge/STI to their organism and key features. Cottage cheese discharge, itchy, pseudohyphae — Candida albicans Frothy