Comprehensive Cancer Biology and Medical Sciences Study Notes

Definition and Essential Oncology Terminology

Cancer refers to a diverse group of diseases primarily defined by the uncontrolled proliferation and dissemination of abnormal cells. Unlike healthy cells, which adhere to a regulated sequence of growth, division, and programmed death known as apoptosis, cancer cells acquire genetic mutations. These mutations enable cells to divide indefinitely, evade detection by the immune system, invade adjacent tissues, and migrate to distant organs, a process termed metastasis.

Key terminology includes the Tumour or Neoplasm, which is an abnormal mass of tissue resulting from uncontrolled cell proliferation; these can be classified as benign or malignant. Benign tumours are non-cancerous, localized, and do not invade surrounding tissues or metastasize. Examples include lipomas or uterine fibroids. Malignant tumours are cancerous, characterized by rapid growth, poor differentiation, and the capacity for invasion and metastasis via blood or lymphatic vessels. Carcinogenesis is the specific process through which normal cells transform into cancer cells via accumulated genetic or epigenetic alterations.

Genetic drivers include the Oncogene, a mutated proto-oncogene that gains function to promote uncontrolled growth (e.g., $RAS$, $MYC$), and the Tumour Suppressor Gene, which normally inhibits division or repairs DNA. A loss-of-function mutation in genes like $TP53$ or $BRCA1$ leads to unchecked proliferation. To support their growth, tumours induce Angiogenesis, the formation of new blood vessels, often through the secretion of Vascular Endothelial Growth Factor ($\text{VEGF}$). Other critical terms include Differentiation, describing how closely cancer cells resemble their host tissue; In Situ Cancer, which is confined to its original site; and the distinction between Driver Mutations (which contribute to development) and Passenger Mutations (present but non-contributing).

The Cell Cycle and Multistep Carcinogenesis

The cell cycle is the ordered sequence of events by which a cell duplicates its contents and divides. It is regulated by cyclins, cyclin-dependent kinases ($\text{CDKs}$), and checkpoint proteins. The cycle comprises specific phases: $G1$ (Gap 1), where the cell enlarges and synthesizes proteins while passing the Restriction Point ($R\text{-point}$); the $S$ phase (Synthesis), where DNA replication results in each of the $46$ chromosomes being duplicated to produce $92$ chromatids; $G2$ (Gap 2), for further growth and organelle duplication; and the $M$ phase (Mitosis), where the cell divides through prophase, metaphase, anaphase, and telophase. Cells may also enter $G0$, a resting state which can be permanent (neurons) or temporary (liver cells).

Regulatory checkpoints ensure the fidelity of this process. The $G1/S$ Checkpoint ($R\text{-point}$) assesses cell size, nutrients, and DNA integrity using proteins such as $RB$ protein, $p53$, $p21$, and the $\text{CDK4/6-Cyclin D}$ complex. The $G2/M$ Checkpoint ensures DNA is fully replicated using $\text{CDK1-Cyclin B}$ and $\text{ATM/ATR}$ kinases. The Spindle Assembly Checkpoint in the $M$ phase ensures chromosome attachment to spindle fibers via $MAD1/MAD2$ and $BubR1$.

Carcinogenesis is a multistep process requiring the accumulation of genetic changes over decades. It begins with Initiation, where a mutagen causes an irreversible DNA mutation in a critical gene. This is followed by Promotion, where repeated mitogenic signals lead to clonal expansion of the initiated cell. Progression occurs as further genetic instability grants malignant properties like invasion and angiogenesis. The final step is Metastasis, where cells survive transit through blood or lymph to colonize distant organs.

Comparison of Oncogenes and Tumour Suppressor Genes

Oncogenes and tumour suppressor genes have opposing roles in cell regulation. Oncogenes promote controlled proliferation in their normal state (proto-oncogenes). When they undergo a gain-of-function (dominant) mutation, a single mutant copy is sufficient to permanently accelerate cell division, akin to a stuck accelerator pedal in a car. Examples include $RAS$, $MYC$, $HER2$, and $BCR-ABL$.

Tumour suppressor genes normally inhibit growth, repair DNA, or trigger apoptosis. They require loss-of-function mutations in both alleles to cause cancer, as described by the Knudson 2-hit hypothesis (recessive at the cellular level). This is analogous to a cut brake cable. Key examples include $TP53$, $BRCA1$, $BRCA2$, $RB1$, $APC$, and $PTEN$.

The Ten Hallmarks of Cancer (Hanahan and Weinberg)

The hallmarks framework describes the biological capabilities cancer cells acquire. Sustaining Proliferative Signalling involves producing autocrine growth signals or constitutively active receptors; for example, mutated $RAS$ permanently activates the $\text{MAPK/ERK}$ pathway. Evading Growth Suppressors involves bypassing checkpoints, such as the loss of $RB$ protein removing the $G1/S$ brake. Resisting Cell Death is achieved by overexpressing anti-apoptotic agents like $BCL-2$ or losing $TP53$.

Enabling Replicative Immortality occurs via the reactivation of telomerase ($hTERT$), which prevents telomere shortening and allows division beyond the Hayflick limit of approximately $50$ divisions. Inducing Angiogenesis involves secreting $\text{VEGF}$ and $\text{FGF}$ to supply oxygen and nutrients. Activating Invasion and Metastasis involves the loss of $E\text{-cadherin}$ for adhesion and the secretion of matrix metalloproteinases ($\text{MMPs}$).

Other hallmarks include Reprogramming Energy Metabolism, specifically the Warburg Effect, where cells use aerobic glycolysis for rapid ATP and biosynthetic precursors. Evading Immune Destruction is managed by downregulating $\text{MHC-I}$ or expressing $PD\text{-L1}$. Genomic Instability arises from defects in DNA repair (e.g., $MMR$, $NER$, or homologous recombination). Finally, Tumour-Promoting Inflammation creates a microenvironment rich in growth factors and mutagenic reactive oxygen species ($\text{ROS}$), such as in $H.\text{ pylori}$ infections.

Causes and Risk Factors

Carcinogenic agents are classified into several categories. Chemical carcinogens like tobacco smoke (containing benzopyrene), asbestos, and aflatoxin $B1$ (from Aspergillus) form DNA adducts. Aflatoxin specifically causes a $G:C$ to $T:A$ transversion in the $TP53$ codon $249$. Physical carcinogens include UV radiation ($UVB$), which causes pyrimidine dimers ($C\text{-C}$ or $T\text{-T}$), and ionising radiation ($X\text{-rays}$, gamma rays, radon), which causes double-strand DNA breaks.

Biological agents include viruses like $HPV\text{ 16/18}$ (cervical), $HBV/HCV$ (liver), and $EBV$ (lymphoma). Viral oncoproteins like $HPV\text{ E6}$ degrade $p53$, while $E7$ inactivates $RB$. Bacteria such as $Helicobacter\text{ pylori}$ cause gastric cancer via chronic inflammation. Genetic factors include germline mutations in $BRCA1/2$, $APC$, or $TP53$ (Li-Fraumeni syndrome). Hormonal factors, such as oestrogen exposure, act via mitogenic signalling. Lifestyle factors like obesity (raising $IGF\text{-1}$), alcohol (acetaldehyde adducts), and red meat also contribute. Finally, immunosuppression (HIV or transplant) impairs immune surveillance, allowing malignant clones to escape detection.

Classification and Types of Cancer

Cancers are classified by their tissue of origin. Carcinomas ($∼85$% of cases) arise from epithelial cells, including lung adenocarcinoma and breast ductal carcinoma. Sarcomas originate in connective tissues like bone (osteosarcoma) or fat (liposarcoma). Leukaemia involves haematopoietic blood-forming cells in the bone marrow. Lymphomas arise in lymphocytes within lymph nodes (e.g., Hodgkin vs. Non-Hodgkin). Myeloma involves plasma cells and is characterized by $M\text{-proteins}$ and bone lesions. CNS tumours arise from glial cells or neurons, such as Glioblastoma multiforme. Germ cell tumours originate in gonadal or extragonadal sites, and Neuroendocrine Tumours ($\text{NETs}$) involve hormone-secreting cells, such as small cell lung cancer.

Leukaemia represents a significant subset with distinct characteristics. Acute leukaemias ($\text{AML/ALL}$) present with immature blast cells ($>20$% in marrow) and have a rapid onset of weeks, leading to severe bone marrow failure. $ALL$ is most common in children aged $2-5$, while $AML$ typically affects adults over $60$. Chronic leukaemias ($\text{CML/CLL}$) involve mature but abnormal cells, have a slow onset over years, and may be asymptomatic at diagnosis. $CML$ is defined by the Philadelphia chromosome $t(9;22)$ in nearly all cases.

Staging and Grading of Cancer

Staging defines the extent of disease spread, primarily using the TNM System. $T$ (Tumour) indicates size and local extension ($T0$ to $T4$). $N$ (Nodes) denotes regional lymph node involvement ($N0$ to $N3$). $M$ (Metastasis) specifies the presence of distant spread ($M0$ or $M1$). Overall groups range from Stage $0$ (In Situ, near $100$% survival) to Stage $IV$ (distant metastasis present, usually incurable/palliative).

Grading describes the microscopic appearance and aggressiveness. Grade $1$ (Well-differentiated) cells closely resemble normal tissue and are slow-growing. Grade $2$ is intermediate. Grade $3$ (Poorly differentiated) cells look markedly abnormal and grow rapidly. Grade $4$ (Undifferentiated/Anaplastic) cells bear no resemblance to the tissue of origin and are highly aggressive.

Common Cancers: Profiles and Examples

Breast Cancer is the most common cancer in women, often arising from ductal cells ($∼75$%). Risk factors include $BRCA$ mutations and high oestrogen exposure. Symptoms include a painless lump or skin dimpling ($\text{peau d'orange}$). Treatment involves surgery, radiotherapy, and targeted agents like tamoxifen for $ER+$ or trastuzumab for $HER2+$.

Lung Cancer is the leading cause of cancer death. Small Cell Lung Cancer ($\text{SCLC}$) is neuroendocrine and aggressive, while Non-Small Cell Lung Cancer ($\text{NSCLC}$) includes adenocarcinoma and squamous cell. Smoking causes approximately $85$% of cases. Symptoms include persistent cough and haemoptysis. Treatment involves lobectomy for early stages, platinum-based chemo, and targeted inhibitors like erlotinib for $EGFR$ mutations.

Colorectal Cancer follows an adenoma-carcinoma sequence over $10-15$ years. Risks include $APC$ mutations, Lynch syndrome, and high-fat diets. Symptoms include rectal bleeding and changes in bowel habits. Treatment includes resection and $FOLFOX/FOLFIRI$ chemotherapy.

Cervical Cancer is almost entirely caused by persistent $HPV$ infection. It progresses from $CIN\text{ 1-3}$ and is treated via radical hysterectomy or concurrent chemoradiotherapy ($\text{cisplatin} + \text{EBRT}$). PREVENTION is achieved via the $Gardasil\text{-9}$ vaccine.

Prostate Cancer is the most common in men and is often slow-growing. Age over $50$ and family history ($BRCA2$) are major risks. Symptoms include Lower Urinary Tract Symptoms ($\text{LUTS}$). Treatments range from active surveillance to androgen deprivation therapy using $LHRH$ agonists like leuprorelin.

Acute Lymphoblastic Leukaemia ($\text{ALL}$) peak incidence occurs in children aged $2-5$. Pathophysiology includes marrow expansion causing bone pain and blast cell accumulation causing anaemia (pallor) and thrombocytopenia (bruising). Treatment is multi-phasic: induction, consolidation, and long-term maintenance with methotrexate and 6\text{-mercaptopurine.

Melanoma is a highly aggressive cancer of melanocytes, often driven by the $BRAF\text{ V600E}$ mutation. It follows the ABCDE criteria: Asymmetry, Border irregularity, Colour variation, Diameter $>6\text{mm}$, and Evolution. Treatment includes wide local excision and immunotherapy with $PD\text{-1}$ inhibitors.

Signs, Symptoms, and Diagnostics

The CAUTION mnemonic summarizes general warning signs: Change in bowel/bladder habits; A sore that does not heal; Unusual bleeding/discharge; Thickening or lump; Indigestion/dysphagia; Obvious change in a wart/mole; and Nagging cough/hoarseness.

Diagnostic investigations include Biopsies for definitive histology, and Blood Tests for tumour markers like $PSA$ (prostate), $CEA$ (colorectal), and $CA\text{-125}$ (ovarian). Imaging techniques include CT for staging, MRI for soft tissue detail (brain/prostate), and PET-CT utilizing ${}^{18}\text{F-FDG}$, a radioactive glucose analogue taken up by metabolically active cells. Endoscopy/Colonoscopy provides direct visualization and biopsy. Mammography is used for population screening ($\text{ages 40-74}$). Molecular testing ($\text{NGS}$, $\text{FISH}$) guides targeted therapy by identifying mutations like $EGFR$ or $ALK$ rearrangements.

Treatment Modalities and Pharmacology

Surgery remains a primary curative modality, though it is also used for debulking or palliation. Radiotherapy uses ionizing radiation to cause double-strand DNA breaks. Fractionation exploits the 4 Rs of Radiobiology: Repair (of normal tissue), Repopulation, Redistribution (into sensitive phases), and Reoxygenation.

Chemotherapy classes include Alkylating Agents ($\text{cyclophosphamide, cisplatin}$) which cross-link DNA; Antimetabolites ($\text{methotrexate, 5-FU}$) which inhibit DNA synthesis; Anthracyclines ($\text{doxorubicin}$) which generate free radicals and inhibit topoisomerase II; Vinca Alkaloids ($\text{vincristine}$) which inhibit microtubule polymerization; and Taxanes ($\text{paclitaxel}$) which prevent depolymerization. Platinum compounds like cisplatin form bulky intra-strand DNA adducts.

Targeted therapies focus on specific molecules: Imatinib targets $BCR-ABL$ in $CML$; Trastuzumab targets $HER2$; Bevacizumab targets $\text{VEGF-A}$ to block angiogenesis; and Olaparib is a PARP inhibitor using synthetic lethality in $BRCA\text{-mutant}$ cancers.

Immunotherapy includes Immune Checkpoint Inhibitors like Pembrolizumab (anti-$PD\text{-1}$) and Ipilimumab (anti-$CTLA\text{-4}$). CAR-T Cell Therapy involves engineering a patient's T-cells to target antigens like $CD19$. Hormone therapy includes Tamoxifen ($\text{SERM}$) and Aromatase inhibitors for breast cancer, and $LHRH$ agonists for prostate cancer.

Stem Cell Transplantation can be Autologous (patient's own cells for dose intensification) or Allogeneic (donor cells). Allogeneic transplants provide a Graft-versus-Leukaemia ($\text{GVL}$) effect but carry the risk of Graft-versus-Host Disease ($\text{GVHD}$).

Cancer Prevention and Epidemiology

Prevention occurs at three levels. Primary Prevention eliminates risk factors before disease (e.g., vaccine, smoking cessation). Secondary Prevention involves early detection (e.g., Pap smear, mammography). Tertiary Prevention prevents progression in confirmed patients (e.g., adjuvant chemo).

Key modifiable risk factors include tobacco smoking, which accounts for approximately $22$% of global cancer deaths; obesity ($∼5-8$% of cancers); and alcohol ($∼5$%). UV radiation is responsible for approximately $90$% of non-melanoma skin cancers. $HPV$ infection is linked to $99.7$% of cervical cancers.

Scenario and Critical Thinking Q&A

Question 1: Difference between benign and malignant? Answer: Benign is slow-growing, encapsulated, and non-invasive (e.g., lipoma). Malignant is rapidly growing, invasive, and can metastasize (e.g., invasive ductal carcinoma).

Question 2: Knudson two-hit hypothesis? Answer: Both alleles of a tumour suppressor gene must be inactivated. One may be germline (inherited), and the second is somatic (acquired). This explains early onset in hereditary cases.

Question 3: Telomerase reactivation? Answer: Normal cells stop at the Hayflick limit. Cancer cells reactivate telomerase to achieve replicative immortality. Without it, they would reach senescence and die.

Question 4: Grade 3, Stage II Breast Cancer? Answer: Grade measures aggressiveness (under microscope); Grade 3 means very abnormal/fast-growing. Stage measures spread; Stage II means localized spread but no distant metastasis.

Question 5: $RAS$ (G12V) significance? Answer: $RAS$ is a molecular switch. This point mutation locks it in the "ON" state, continuously activating $\text{MAPK/ERK}$ and $\text{PI3K/AKT}$ pathways without external signals.

Question 6: 6-year-old Symptoms (ALL)? Answer: Pallor indicates anaemia due to blast cells crowding out marrow. Bruising indicates thrombocytopenia. Bone pain is from marrow expansion. Infections occur because elevated WBCs are non-functional blasts.

Question 7: $HER2$ Trastuzumab resistance? Answer: Mechanisms include MUC4 overexpression blocking binding, $HER2$ shedding (p95 fragment), or downstream $PIK3CA$ mutations. Second-line is T-DM1 or T-DXd.

Question 8: Vaccine failure (HPV)? Answer: Not necessarily failure. The vaccine covers specific types ($∼85$%). It won't prevent non-covered types, pre-existing infections, or compensate for missed screenings.

Question 9: Warburg Effect and PET? Answer: Cancer cells prefer aerobic glycolysis for speed and biosynthetic precursors. PET scans exploit this by injecting radioactive glucose analogue (${}^{18}\text{F-FDG}$), which accumulates in these hyper-metabolic cells.

Question 10: $BRCA1$ counseling? Answer: Carriers have a $55-72$% lifetime breast cancer risk. Management includes annual MRI, risk-reducing bilateral mastectomy, and salpingo-oophorectomy after childbearing.

Question 11: Metastatic journey? Answer: (1) Local invasion (loss of $E\text{-cadherin}$, transition to mesenchymal phenotype); (2) Intravasation; (3) Survival in circulation (platelet cloaks); (4) Arrest in liver (honing via $CXCR4$ and $CXCL12$); (5) Extravasation; (6) Dormancy; (7) Colonization/Angiogenesis.

Question 12: Synthetic lethality? Answer: Combining PARP inhibition with $BRCA$ deficiency. Cancer cells lack Homologous Recombination ($\text{HR}$); inhibiting PARP prevents base excision repair, leading to catastrophic DNA breaks and cell death. Normal cells survive because their $BRCA$ genes are intact.

Question 13: Gender-neutral HPV vaccination? Answer: Arguments include protecting males from oropharyngeal/anal cancer, improving herd immunity for women, and specifically protecting MSM populations not covered by female-only programs.

Question 14: Pembrolizumab resistance? Answer: It blocks $PD\text{-1:PD-L1}$ interactions. Resistance occurs via loss of tumour antigenicity, downregulation of $\text{MHC-I}$ (specifically $B2M$ deletions), or upregulation of alternative checkpoints (e.g., $TIM-3, LAG-3$).

Question 15: Fever of $38.5^∘\text{C}$ on Day 10 (CHOP)? Answer: This is febrile neutropenia, a medical emergency. Chemotherapy nadir leaves the patient with Absolute Neutrophil Count ($\text{ANC}$) $<0.5 \times 10^9/L$. Management requires antibiotics within one hour to prevent sepsis mortality ($>50$% if untreated).

Question 16: Integrative Case (KRAS G12C)? Answer: Diagnosis is NSCLC Stage IVA ($T2a, N2, M1b$). The $KRAS\text{ G12C}$ mutation creates a specific covalent drug-binding pocket. Treatment includes targeted sotorasib or adagrasib, alongside carboplatin and immunotherapy.