Carcinogenesis — Oncogenes and Tumor Suppressor Genes

Oncogenes: Gain-of-Function Mutations

• Point mutations creating constitutively active proteins (e.g., RAS mutations in ~30% of human cancers producing permanently GTP-bound, signaling-active protein; BRAF V600E in melanoma causing continuous MAPK pathway activation)
• Gene amplification producing excessive protein quantity (e.g., HER2/neu amplification in ~20% of breast cancers, MYC amplification in Burkitt lymphoma)
• Chromosomal translocation juxtaposing oncogenes to highly active promoters (e.g., t(9;22) Philadelphia chromosome in chronic myeloid leukemia producing BCR-ABL fusion protein with constitutive tyrosine kinase activity; t(8;14) in Burkitt lymphoma placing MYC under immunoglobulin heavy chain promoter control)
• Insertional activation by retroviruses or transposons disrupting normal gene regulation

Tumor Suppressor Genes: Loss-of-Function Mutations

• Point mutations and frameshift mutations producing truncated, non-functional proteins
• Gene deletions eliminating entire chromosomal segments (monosomy of chromosome 17p in p53-mutant tumors)
• Hypermethylation of CpG-rich promoter regions silencing gene expression epigenetically (e.g., VHL methylation in renal cell carcinoma)
• Chromosomal rearrangements disrupting coding sequences
• Loss of heterozygosity (LOH) where inherited mutation in one allele is followed by somatic loss or mutation of the remaining wild-type allele (classical two-hit pattern)

Critical tumor suppressors and their functions

• p53 ("Guardian of the Genome"): Transcription factor activated by DNA damage, hypoxia, and oncogenic stress; induces cell cycle arrest (via p21 CDKN1A), apoptosis, or senescence; mutated in >50% of human cancers; Li-Fraumeni syndrome (germline p53 mutations) predisposes to early-onset diverse malignancies
• RB (Retinoblastoma protein): Negative regulator of G1/S checkpoint; hypophosphorylated RB binds E2F transcription factors blocking S-phase genes; inactivated in retinoblastoma, osteosarcoma, and lung cancer; "two-hit" disease classically affects both eyes (hereditary form)
• PTEN: Phosphatase antagonizing PI3K/AKT pathway; loss promotes survival signaling; mutated in Cowden syndrome (breast/thyroid cancer predisposition)
• APC (Adenomatous Polyposis Coli): Regulates Wnt/β-catenin signaling; loss causes familial adenomatous polyposis (hundreds of colonic polyps by age 20); biallelic loss critical in colorectal cancer development
• BRCA1/BRCA2: DNA repair proteins (homologous recombination); germline mutations confer 70% lifetime breast cancer risk and 40% ovarian cancer risk; somatic mutations in sporadic breast/ovarian cancers
• MLH1, MSH2, MSH6, PMS2: Mismatch repair (MMR) proteins; loss causes Lynch syndrome (hereditary nonpolyposis colorectal cancer) with microsatellite instability
• VHL: E3 ubiquitin ligase regulating HIF-1α stability; loss causes von Hippel-Lindau syndrome (renal cell carcinoma, hemangioblastoma)
• NF1: RAS GTPase-activating protein; loss causes neurofibromatosis type 1 with increased optic pathway gliomas and malignant peripheral nerve sheath tumors

Multi-Step Carcinogenesis Model

• Activation of oncogenic pathways: RAS, MYC, PI3K/AKT, Wnt/β-catenin
• Inactivation of growth-suppressive pathways: p53, RB, APC, PTEN
• Evasion of apoptosis: BCL2 overexpression, death receptor pathway inactivation
• Unlimited replicative potential: TERT/telomerase activation, ATRX inactivation
• Sustained angiogenesis: VEGF upregulation, HIF-1α activation
• Invasion and metastasis: Loss of E-cadherin (CDH1), activation of epithelial-mesenchymal transition (EMT)

Inherited Genetic Predisposition

• Hereditary cancer syndromes with germline mutations in tumor suppressors:
• Li-Fraumeni syndrome (p53): Sarcomas, breast, brain, leukemias, adrenocortical carcinomas; average cancer age <45 years
• Familial Adenomatous Polyposis (APC): Colorectal cancer nearly 100% by age 40 without intervention
• Lynch Syndrome (MLH1, MSH2, MSH6, PMS2): Colorectal cancer 70% lifetime risk, endometrial cancer 40%
• Hereditary Breast and Ovarian Cancer (BRCA1/BRCA2): Breast cancer 45-87% lifetime risk depending on mutation and age; ovarian cancer 10-54%
• Familial Retinoblastoma (RB): Bilateral ocular involvement in ~40% of inherited cases
• von Hippel-Lindau syndrome (VHL): Renal cell carcinoma, pheochromocytoma, hemangioblastoma
• Cowden syndrome (PTEN): Breast and thyroid cancers
• Neurofibromatosis type 1 (NF1): Optic pathway gliomas, malignant peripheral nerve sheath tumors, other cancers

Environmental Carcinogens (Acquiring Oncogenic Mutations)

• Chemical carcinogens: Tobacco smoke (lung, bladder cancers via KRAS/TP53 mutations), aromatic amines (bladder), polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds (gastric)
• Radiation: Ionizing radiation causes double-strand breaks activating p53-mediated apoptosis or genomic instability; UV radiation causes thymine dimers (skin cancers via BRAF mutations)
• Viral oncogenic proteins: Human papillomavirus (HPV E6 inactivates p53, E7 inactivates RB → cervical cancer); Hepatitis B and C (cirrhosis → HCC with TP53/CTNNB1 mutations); Epstein-Barr virus (EBV); Human T-cell lymphotropic virus 1 (HTLV-1); Kaposi sarcoma-associated herpesvirus (KSHV)
• Chronic inflammation: Barrett esophagus (chronic reflux → adenocarcinoma), inflammatory bowel disease (colorectal cancer via IL-6/STAT3 pathway)
• Occupational exposures: Asbestos (mesothelioma via p16 inactivation), benzene (acute myeloid leukemia), beryllium
• Lifestyle factors: Excessive alcohol (hepatocellular carcinoma, esophageal/colorectal cancers), obesity (estrogen-dependent cancers, colorectal)
• Iatrogenic: Alkylating agents, topoisomerase inhibitors (secondary leukemias); hormonal therapy (endometrial cancer)

Biological Risk Factors

• Chronic proliferative states: Barrett esophagus, chronic hepatitis, ulcerative colitis—increased cell division provides opportunities for mutation
• DNA repair deficiencies: Xeroderma pigmentosum (nucleotide excision repair defect → 1000-fold skin cancer increase), Lynch syndrome, BRCA mutations
• Genomic instability syndromes: Ataxia-telangiectasia (ATM gene), Bloom syndrome (BLM helicase)
• Immune deficiency: AIDS patients 100-fold increased lymphoma risk; transplant recipients with chronic immunosuppression

Early Neoplastic Changes

• Dysplasia without invasion: Cervical intraepithelial neoplasia (CIN) from HPV infection; Barrett esophagus with dysplasia; ductal carcinoma in situ (DCIS) of breast—dysplastic epithelium with increased nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, increased mitotic figures, and loss of normal maturation
• Adenomatous polyps: Multiple polyps in familial adenomatous polyposis clinically asymptomatic but histologically showing adenomatous changes with nuclear stratification and mucin depletion
• Atypical skin lesions: Dysplastic nevi with irregular borders, color variation, larger size (>6 mm)—precursors in melanoma-prone individuals

Established Malignancy—Organ-Specific Presentations

Lung cancer (KRAS/TP53/EGFR mutations)

• Persistent cough, hemoptysis
• Chest pain (pleural involvement)
• Dyspnea from airway obstruction or pleural effusion
• Histologically: Squamous cell carcinoma (central, keratinization), adenocarcinoma (peripheral, mucin production), small cell (neuroendocrine), large cell carcinoma

Breast cancer (HER2 amplification/TP53/BRCA mutations)

• Painless mass, nipple discharge (esp. if bloody from intraductal component)
• Skin dimpling, retraction (invasion of suspensory ligaments)
• Axillary lymphadenopathy (metastatic involvement)
• Histologically: Invasive ductal carcinoma (most common, glandular structures invading stroma), invasive lobular carcinoma (single-file pattern, diffuse)
• Molecular: HER2 amplification (immunohistochemistry 3+ or FISH positive) guides trastuzumab therapy; hormone receptor status (ER/PR) determines endocrine therapy eligibility

Colorectal cancer (APC/KRAS/TP53 mutations)

• Left-sided lesions: Altered bowel habits, narrowed stools ("apple core" appearance), obstruction
• Right-sided lesions: Anemia from chronic occult bleeding, palpable mass, less likely obstruction
• Abdominal pain, weight loss in advanced disease
• Histologically: Adenocarcinoma with glandular differentiation, mucin production; grade based on differentiation; mucinous adenocarcinoma shows abundant extracellular mucin with floating tumor cells
• Gross: Ulcerated, infiltrative lesion with raised borders (malignant-appearing)

Cervical cancer (HPV E6/E7 inactivating p53/RB)

• Abnormal vaginal bleeding, postcoital bleeding
• Vaginal discharge (often blood-tinged, foul-smelling from necrotic tissue)
• Pelvic pain (advanced disease with parametrial involvement)
• Cytology/histology: CIN (dysplasia) → invasive squamous cell carcinoma (keratinization, intercellular bridges) or adenocarcinoma (columnar with mucin)
• Gross: Exophytic mass or endophytic ulcer, friable, bleeding easily

Melanoma (BRAF V600E/NRAS/TP53 mutations)

• Irregular dark lesion with color variation, asymmetry, enlargement over months
• Bleeding, itching, non-healing ulceration
• Histologically: Atypical melanocytes in basal layer (junctional component) extending into dermis (invasive component); Breslow depth (thickness in mm) critical prognostic factor; Clark level (depth relative to skin layers) determines staging
• Gross: Dark, raised, irregular borders with possible ulceration

Renal cell carcinoma (VHL mutation)

• Classic triad (now rare at presentation): Flank pain, hematuria, palpable mass
• Often asymptomatic, discovered incidentally on imaging
• Constitutional symptoms: Fever, weight loss, night sweats
• Gross: Golden-yellow color from lipid-rich cytoplasm (clear cells); hemorrhage, necrosis
• Histologically: Clear cell carcinoma (most common, lipid-rich cytoplasm); granular cell type; sarcomatoid (poor prognosis)

Hepatocellular carcinoma (p53/CTNNB1 mutations in cirrhotic livers)

• Right upper quadrant pain, hepatomegaly
• Ascites, variceal bleeding from portal hypertension
• Jaundice (biliary obstruction)
• Gross: Nodular lesions in cirrhotic liver, tan-yellow to green (bile staining)
• Histologically: Dysplastic nodules → well-differentiated HCC → advanced HCC with loss of hepatic architecture

Acute leukemias (KRAS/TP53/FLT3 mutations in myeloid; MLL rearrangements in lymphoid)

• Bleeding (thrombocytopenia from blast predominance)
• Infections (neutropenia, immature WBC dysfunction)
• Fatigue, dyspnea (anemia)
• Lymphadenopathy, hepatosplenomegaly
• Peripheral blood/bone marrow: Blasts >20% (diagnostic threshold); Auer rods (pathognomonic in AML—cytoplasmic inclusions of Auer rod material)
• Histologically: Sheets of immature cells, high mitotic rate, scant cytoplasm, high nuclear-to-cytoplasmic ratio

Laboratory and Imaging Correlates

• Tumor markers: Elevated PS

Establishing the malignancy first

• Tissue biopsy with histopathology remains the gold standard; molecular testing is performed on the diagnostic specimen, never in place of it. A notable exception is retinoblastoma, diagnosed clinically by leukocoria plus examination under anesthesia and MRI — percutaneous biopsy is avoided because of tumor seeding risk.
• Cytogenetics/FISH for balanced translocations: t(9;22) Philadelphia chromosome in CML, t(8;14) in Burkitt lymphoma. Quantitative RT-PCR for BCR-ABL1 transcripts reported on the International Scale is the confirmatory and monitoring assay.

Somatic (tumor) molecular profiling

• Immunohistochemistry is the screening tier: HER2 IHC 0/1+ negative, 3+ positive, 2+ equivocal and reflexed to ISH, with an HER2/CEP17 ratio ≥2.0 supporting amplification (ASCO/CAP HER2 testing guideline). Loss of nuclear staining for MLH1, MSH2, MSH6, or PMS2 indicates mismatch-repair deficiency.
• MSI/dMMR testing on every colorectal and endometrial cancer is recommended universally by NCCN, both to detect Lynch syndrome and to select checkpoint-inhibitor candidates. Isolated MLH1 loss requires BRAF V600E testing or MLH1 promoter hypermethylation studies to exclude a sporadic epigenetic cause.
• Next-generation sequencing panels detect actionable driver alterations (KRAS/NRAS, EGFR, BRAF V600E, ALK, ROS1, BRCA1/2); plasma cell-free DNA ("liquid biopsy") is an accepted alternative when tissue is insufficient.

Germline testing and named criteria

• NCCN Genetic/Familial High-Risk Assessment guidelines define referral thresholds for BRCA1/2 and Lynch testing; USPSTF recommends familial-risk screening tools followed by genetic counseling before testing in women with suggestive family histories.
• Amsterdam II criteria and the revised Bethesda guidelines historically identified Lynch syndrome; universal tumor testing has largely supplanted them.
• Classic Li-Fraumeni criteria and the Chompret criteria trigger germline TP53 testing (early sarcoma, premenopausal breast cancer, adrenocortical carcinoma, choroid plexus tumor).
• Germline results require confirmation on a second, non-tumor sample (typically blood or saliva).

Immediate stabilization (oncologic emergencies first)

• Tumor lysis syndrome in high-turnover, MYC-driven tumors: aggressive IV hydration plus a urate-lowering agent — allopurinol for prophylaxis, rasburicase for established or high-risk disease (contraindicated in G6PD deficiency).
• Febrile neutropenia, malignant spinal cord compression (corticosteroid, e.g., dexamethasone, then urgent radiation/surgery), and superior vena cava syndrome take precedence over any molecular workup.

Genotype-directed first-line therapy

• BCR-ABL tyrosine kinase inhibitors (imatinib): rational therapy for the t(9;22) fusion kinase; response tracked by BCR-ABL1 transcript on the International Scale (NCCN CML guideline).
• Anti-HER2 antibodies (trastuzumab) for IHC 3+/ISH-amplified breast cancer, per ASCO/CAP testing and ASCO/NCCN treatment recommendations.
• EGFR TKIs (osimertinib) for sensitizing EGFR mutations; ALK inhibitors for ALK fusions (NCCN NSCLC).
• BRAF plus MEK inhibitor combinations (vemurafenib/dabrafenib with trametinib) in BRAF V600E melanoma — combination prevents paradoxical MAPK reactivation seen with single-agent BRAF inhibition.
• PARP inhibitors (olaparib) exploit synthetic lethality in BRCA-mutant homologous-recombination-deficient tumors.
• PD-1 checkpoint inhibitors (pembrolizumab) have tissue-agnostic FDA approval for MSI-high/dMMR solid tumors.

Escalation and resistance

• Rebiopsy or repeat liquid biopsy at progression; switch to a next-generation inhibitor active against the resistance allele (e.g., ponatinib for the T315I gatekeeper mutation in CML).

Definitive and risk-reducing surgery

• Prophylactic total colectomy in FAP and risk-reducing bilateral salpingo-oophorectomy (with consideration of mastectomy) in BRCA carriers, timed per NCCN.

Prevention and contraindications

• HPV vaccination (ACIP/CDC) and cervical screening (USPSTF) prevent E6/E7-driven disease.
• Anti-EGFR monoclonals (cetuximab, panitumumab) are contraindicated in RAS-mutant colorectal cancer — the downstream mutation makes receptor blockade futile.
• Avoid radiation where feasible in germline TP53 and hereditary retinoblastoma carriers.

Complications of the underlying genetic lesion

• Clonal evolution and acquired drug resistance: ongoing genomic instability selects escape clones — EGFR T790M or C797S after EGFR TKIs, BCR-ABL T315I after imatinib. Signal: rising transcript level or new radiographic progression on a previously effective drug.
• Metastasis via loss of E-cadherin and EMT: the dominant cause of cancer death; new bone pain, focal neurologic deficit, or hepatomegaly should prompt restaging.
• Malignant transformation of premalignant lesions: FAP progresses to colorectal cancer essentially universally without colectomy; Barrett esophagus with high-grade dysplasia signals imminent adenocarcinoma.
• Second primary cancers in germline carriers: hereditary retinoblastoma survivors develop osteosarcoma, markedly amplified by prior external-beam radiation because the second RB hit occurs in every somatic cell.

Treatment-related complications

• Therapy-related myeloid neoplasm — alkylating agents cause MDS/AML after a longer latency with chromosome 5q/7q loss and TP53 mutation; topoisomerase II inhibitors cause AML with KMT2A (MLL) 11q23 rearrangement after a shorter latency and typically without a preceding myelodysplastic phase.
• Tumor lysis syndrome after cytotoxic therapy of bulky, chemosensitive disease: hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, acute kidney injury. Emergency — hyperkalemia can be immediately fatal.
• Trastuzumab cardiotoxicity: HER2 blockade in cardiomyocytes causes a usually reversible LVEF decline, not dose-dependent, distinct from irreversible dose-dependent anthracycline cardiomyopathy. Serial echocardiographic LVEF monitoring is standard (ASCO cardiac dysfunction guideline).
• Immune-related adverse events from checkpoint inhibitors: colitis, hypophysitis, thyroiditis, hepatitis, pneumonitis; myocarditis is a low-frequency but high-mortality emergency. ASCO/NCCN immunotherapy toxicity guidelines direct high-dose corticosteroids for severe events.
• Cytokine release syndrome after CAR-T/bispecific therapy — fever, hypotension, hypoxia; emergency, treated with the IL-6 receptor antagonist tocilizumab.
• Febrile neutropenia remains the most common life-threatening cytotoxic complication and mandates immediate empiric broad-spectrum antibiotics.

• One hit versus two: oncogenes act dominantly — a single activated allele suffices; tumor suppressors require biallelic inactivation (Knudson two-hit). The classic stem is bilateral, multifocal, early-onset retinoblastoma = germline first hit; unilateral, later-onset = two somatic hits.
• HPV E6 degrades p53, E7 inactivates RB — the highest-yield virology–oncogene link on Step 1. Memorize the pairing direction; reversing E6 and E7 is the standard distractor.
• Best next step after MMR-deficient tumor IHC: if MLH1 protein is absent, test for BRAF V600E or MLH1 promoter hypermethylation before diagnosing Lynch syndrome — a positive result indicates a sporadic epigenetic cause, not a germline mutation.
• RAS mutation contraindicates anti-EGFR antibodies in metastatic colorectal cancer; the constitutively GTP-bound RAS operates downstream of the receptor, so cetuximab cannot work. This is the most commonly tested "do not give" in molecular oncology.
• Synthetic lethality: PARP inhibitors kill BRCA-mutant cells because base-excision repair blockade plus absent homologous recombination is lethal, while heterozygous normal cells survive. Expect olaparib in an ovarian or breast cancer stem.
• **t(9;22) BCR-ABL → imatinib; t(8;14) MYC–IgH → Burkitt with a starry-sky pattern; HER2 amplification → trastuzumab with baseline and serial LVEF.**
• Two secondary-leukemia patterns: alkylators → 5q/7q deletions with a myelodysplastic prodrome; topoisomerase II inhibitors → 11q23/KMT2A rearrangement with short latency.
• Radiation is relatively avoided in germline TP53 (Li-Fraumeni) and hereditary retinoblastoma because every cell already carries the first hit — a stem describing osteosarcoma in a prior radiation field of a retinoblastoma survivor is testing exactly this.