Fundamentals of Neoplasia (Mechanisms of Cancer Development)😊

Fundamentals of Neoplasia
(Mechanisms of Cancer Development)

Cell Cycle Progression:

• Phases: G0 (quiescent) → G1 → S (synthesis) → G2 → M (mitosis).

Timing:

• Variable phases:
• G0, G1 (no fixed time).

• Fixed phases:
• After S → Point of no return
• S (6 hrs), G2 (4 hrs), M (2 hrs)

Phase

• G0 Phase
• Complete resting phase
• Chromosomes condensed

• Interphase (G1–S–G2)
• Chromosomes uncondensed

• G1 Phase
• Pre-synthetic phase
• Proofreading + repair
• Chromosomes uncondensed
• Chromosome arms: 1 long + 1 short arm

• S Phase
• DNA replication
• Chromosomes uncondensed
• Point of no return: S phase (DNA synthesis occurred).

• G2 Phase
• Post-synthetic phase
• Proofreading + repair
• Chromosomes uncondensed

• M Phase
• One diploid cell → two diploid cells
• Chromosomes condensed
• Fate: enter next cycle or go to G0
• Chromosome arms: 2 long + 2 short arms

Stages:

• Metaphase:
• Mitotic spindle forms
• attaches to centromere

• Anaphase:
• Spindle contracts
• centromere breaks

• Chromosomes must be highly condensed

Radiosensitivity and Radioresistance

• Law of Bergonie:
• Actively dividing cells → radiosensitive.
• Non-dividing cells → radioresistant.

• Radiosensitivity by tissue/cell/organ/cycle:

Category	Most Radiosensitive	Most Radioresistant
Cell type	Undifferentiated/ rapidly dividing	Quiscent/ Not dividing
Cell cycle phase	Mitosis (G2/M)	S phase
Organ	Gonads	Vagina (pelvic organ)
Tissue	Bone marrow	Neurons
Blood cell	Lymphocytes	Platelet
Eye	Lens	Sclera
Tumor	Ewing Sarcoma	Osteosarcoma
Testicular tumor	Seminoma	ㅤ

• Radiosensitive Tumors
• Mnemonic: WELMS
• Wilms' tumor.
• Ewing's tumor.
• Lymphoma.
• Multiple myeloma.
• Seminoma (Testicular).
• Ovarian counterpart to seminoma: Dysgerminoma.

• Radioresistant Tumors
• Mnemonic: MORPH
• Melanoma.
• Osteosarcoma.
• RCC.
• Pancreatic cancer.
• HCC.

Inverse Square Law

• Distance vs radiation intensity.

• As distance ↑↑, radiation intensity ↓↓
• If distance is doubled → radiation is 1/2² = 1/4th.
• If distance is tripled → radiation is 1/3² = 1/9th.

Cell Cycle Checkpoints:

• Checkpoint 1: 
• G1 - S junction.
• Phosphorylation of RB gene ("governor"):
• Phosphorylation of RB gene → RB gene inactivation → Loss of tumor suppressor function → Cell cycle don't stop at G1 phase
• Normally active
• Regulates only first checkpoint (G1-S).

• Checkpoint 2: 
• G2 - M junction.

• P53 gene ("policeman"):
• Regulates both checkpoints.

Q. Which of the following is a true statement?

• A. Replication happens in the 'B' phase. In the B phase, the chromosome is highly condensed.

• B. Replication happens in the 'C' phase. In the C phase, the chromosome is highly condensed.

• C. Replication happens in the 'B' phase. In the B phase, the chromosomes in uncondensed.

• D. Replication happens in the 'C' phase. In the C phase, the chromosome is uncondensed.
ANS
• C. Replication happens in the 'B' phase. In the B phase, the chromosomes in uncondensed.

Regulation by Cyclins and CDKs:

• Mnemonic for Cyclin Sequence: Dhoni EK Acha Batsman (D E A B)
• Over runs: 4 6 2 2 1

Cyclin	CDK(s)	ㅤ	ㅤ
Cyclin D	CDK 4, CDK 6	Cyclin D 1 ↳ Mantle cell Lymphoma (NHKL) → t(11:14) → SOX11, CD 5	We gave Dhoni (D), the 1st (D1) mantle (Mantle cell lymphoma) when he put a 6 and 4 (CDK 4, CDK 6)
Cyclin E	CDK 2	ㅤ	ㅤ
Cyclin A	CDK 2	ㅤ	ㅤ
Cyclin B	CDK 1	ㅤ	ㅤ

1. Self-Sufficiency of Growth Signals
(Gain of function mutation)
(Proto-oncogene → Oncogene)

1. Growth Factors

Oncogene / Mutation	Associated Cancers / Syndromes	Mnemonic
PDGF Beta / PDGF Receptor Beta	Brain tumors  (esp. Astrocytoma)	Padikkunna Betakk (PDGF β) → Brain Tumor
HST-1	Osteosarcoma	HST → OST (Osteosarcoma)
HGF (Hepatocyte Growth Factor) / Scatter Factor	Hepatocellular Carcinoma (HCC)	Scatter that Liver

2. Growth factor receptor

Oncogene / Mutation	Associated Cancers / Syndromes	Mnemonic
EGFR1 (ERB-B1)	Adenocarcinoma Lung Ca Colon	(1 → A →A)
EGFR2/ERB-B2 (HER2/neu)	Breast Carcinoma & ovarian cancer	(2→B→B)
ALK on chromosome 2	- Adenocarcinoma Lung,  - Anaplastic Large Cell Lymphoma - Inflammatory Myofibroblastic Tumor - Neuroblastoma	2 dress alakkan (chr 2) ittath → Large Anayude (Large Anaplastic) Adiyil (Adenocar) →
RET on chromosome 10	Medullary Carcinoma Thyroid, MEN 2A/2B	RET 10 MED  MEN (RET gene, Chromosome 10, Medullary Ca Thyroid, MEN 2A/2B)
Ckit (CD117)	GIST, AML,  Mastocytosis,  Melanoma, Seminoma N RAS → AML, Melanoma	Kit for GAMES Get (GIST) A (AML) Kit → for Masturbating () → Semen () Mel (AML, Melan) avathirikkan

• Loss of function of RET gene
• Hirschsprung disease.
• Her2/neu overexpression
• Treatment (Rx): 
• Herceptin,
• Trastuzumab.
• Medullary Carcinoma of thyroid:
• Neuroendocrine tumor
• Parafollicular C Cells
• Histopathology (HPE): 
• Amyloid bodies with calcitonin.

3. Signal transduction proteins

RAS mutations	ㅤ	ㅤ
↳ K-RAS	- Colon cancer,  - Pancreatic cancer,  - Lung cancer (non small cell lung cancers) (thyroid)	K → Couple (CPL) Tumors
↳ H-RAS	- Renal Cell Carcinoma - Bladder cancer - Pituitary Carcinoma - (thyroid)	H → Kidney, bladder, pituitary
↳ N-RAS	- AML - Melanoma	N → M → Mal → aMl, Melanoma
Others	ㅤ	ㅤ
BCR-ABL fusion  • (t 9;22)	230 kDa → CNL 210 KDa → CML 190 KDa → ALL	Bakkar and Abel 9 and 22 years 9 yr old → Likes All (ALL) 22 yr old → Like Camala (CML)
BRAF	Six tumors: - Hairy Cell Leukemia (HCL) - Langerhans Cell Histiocytosis (LCH) - Papillary Ca Thyroid (PCT) - JPA - Colon Ca,  - Melanoma	HCL ⇔ LCH Pct ⇔ jPa Coma (Colon, Melanoma)
Notch	T-ALL	Tall Notch

• KHN → Kitchen RASh
• Most common oncogene affected in malignancy → RAS
• Most common gene affected → p53

4. Nuclear transcription factors :

MYC amplifications	Associated Cancers / Syndromes	Mnemonic
↳ C-MYC	- Burkitt's Lymphoma	(C for Child)
↳ L-MYC	- Small Cell Lung Cancer (L myc, 3p)	(L for Lungs with lot of L)
↳ N-MYC	- Neuroblastoma	(N for Neuroblastoma)

• Clean (CLN) Myc

2. Inactivation of Tumor Suppressor Genes:

• Protective genes inactivated.

P53 gene:

• Chromosome: 17p13.

• P53 → P21 → ⛔ G1 - S

• Congenital Mutation
• Li-Fraumeni Syndrome (autosomal dominant).
• Osteosarcoma
• Retinoblastoma
• Risk for BBB tumors (Bone, Blood, Breast, Brain cancers).

• Diagnosis: 
• Chompret criteria.

• Other similar genes
• P73 gene:
• "big brother" of P53.
• P63
• Helps in Squamous cell differentiation

• Mnemonic:
• Police → Chopra (Chompret) → arrested
• Pearle maney → (Li Fraumeni)
• She was 17 (17p13) when she was on Big Boss (BBB)

RB gene (Retinoblastoma gene):

• Chromosome: 13q14.

• M/c inheritance: Autosomal Dominant (AD).

• Normal form: hypophosphorylated
• Mutation → Retinoblastoma.
• Phosphorylation of RB gene ("governor"):
• Phosphorylation of RB gene → RB gene inactivation → Loss of tumor suppressor function → Cell cycle don't stop at G1 phase
• Normally active
• Regulates only first checkpoint (G1-S).

• Clinical Feature
• Leukocoria

• Knudson's Two-Hit Hypothesis.
• Tumor presents only on loss of heterozygosity.

• Malignancy:
• M/c 2ndary malignancy: Osteosarcoma >>
• M/c primary malignancy: PNET/pineoblastoma

• Types of Retinoblastoma:
• Familial:
• Both eyes
• Increased risk of osteosarcoma >>> Pinealoblastoma 
  (trilateral retinoblastoma),
• Sporadic:
• More common
• One eye only.

• Mnemonic:
• Knudson was the governer →
• He lost his 2 eyes () with 2 hits (2 hit hypothesis) by an assasin
• 2 eyes represent → 2 children → 13 and 14 years old (chromosome 13,14))
• He took revenge by opening third eye (Trilateral → Pinealoblast)
• Assasin nte bone chaaramaaki (Osteosarcoma)
• Assasin → Christian (Vincristine) arrnnu, ayalde topside (etoposide) carbon (carboplatin) aakki

• Clinical Features:
• Leukocoria (M/c).
• Squint (2nd M/c).
• 2ndry glaucoma + Buphthalmos (3rd M/c).

• Spread:
• Direct through optic nerve
• ?? Hematogenous spread → Primary mode??

• CT scan (IOC):
• Shows calcified tumor.
• M/c cause of intraocular calcification.

• Biopsy (Gold standard):
• Sample: Optic nerve.
• Findings:
• Homer wright rosettes (pseudo-rosettes).
• Fleurettes.
• Flexner wintersteiner rosette:
• Empty central lumen with surrounding cells
• nucleus pointing centrally.

• Treatment: 
• B/L → TOC:
• NACT → Sx
• Enucleation (TOC)
• Removal of eyeball + optic nerve
• Chemotherapy
• Vincristine, carboplatin, and etoposide

PTEN gene:

• Chromosome: 10.

• Mutation → Cowden Syndrome
• Mnemonic: Pottan fell in cowdung

• Cowden Syndrome Cancers: 
• Endometrial carcinoma (EN)
• Thyroid tumors (T)
• Trichilemmoma (skin) (T)
• Intestinal polyps (P)
• Breast cancer (b)

• Mnemonic: Pottan fell in Cowdung → remember Cow
1. Milk → breast cancer
2. Give birth → endometrial cancer
3. Tail hair → Trichelloma
4. Eat → Intestine polyp

Other Tumor Suppressor Genes and Chromosomes:

3. Limitless Replicative Potential:

• Cancer cells divide indefinitely,

• often via telomerase expression.

4. Escape Apoptosis:

• Evade programmed cell death by
• increasing anti-apoptotic factors

• t(14;18) translocation
• ↑ BCL-2 (anti-apoptotic)
• ↓ Apoptosis
• ↑ Cell Proliferation → Follicular Lymphoma

• Mnemonic: Friends (Follicular Lymphoma) escape death together

5. Sustained Angiogenesis:

• Induce new blood vessel formation.

• Pro-angiogenic factors
• ↑ Blood supply 
• VEGF, PDGF, FGF.

• Anti-angiogenic factors
• ↓ Blood supply 
• Vasculostatin,
• Endostatin,
• Angiostatin,
• Thrombospondin.

6. Invasion and Metastasis

• Mechanism:
• Loss of E-cadherin (cell detachment).
• Integrin binding to Extracellular Matrix (ECM).
• ECM Degradation: MMPs (2,9), Type IV Collagenase, Cathepsins, Urokinase.
• Epithelial-Mesenchymal Transition (EMT) via SNAIL, TWIST.
• Intravasation (forming tumor emboli with platelets) → Extravasation.

CDH gene (E-cadherin):

• Chromosome 16

• "Glue" for cell-to-cell connection.

Loss/mutation

• Mnemonic: Kadich (CDH) → Breastlum Vyarilum

• "Golu" tumors/Kadicha tumors
1. Diffuse Gastric Cancer

Lauren's Classification	Intestinal Lauren's Classification	Diffuse Lauren's Classification
Epidemiological	Environmental	Familial
Pathology	Gastric atrophy, intestinal metaplasia	Blood Group A
Sex	m > F	F > M
Age	↑ Incidence with ↑Age	Younger age
Morphology	Gland formation Round glands	Poorly differentiated
Cell Type	ㅤ	• Gross: Linitis plastica  ("leather bottle appearance"). • Microscopy: Signet ring cells.
Genetics	APC gene mutations, Microsatellite instability p53, p16 inactivation	Loss of E-cadherin (↓ E-cadherin) p53, p16 inactivation
Invasion	Hematogenous spread	Transmural/Lymphatic spread

2. Lobular Carcinoma Breast
• Indian File/Single File Pattern

• Mnemonic: File (Indian file) of Breast Ca patients
3. Claudin low → EMT positive breast cancer

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• Krukenberg tumor
• Stomach > Breast/ Colon
• Signet Ring Cells
• Retrograde lymphatic spread

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NOTE: Miscellaneous one liners

7. DNA Repair Defects:

Warburg Effect (Aerobic Glycolysis in cancer cells):

Miscellaneous terms	Features
Pasteur Effect	In presence of O₂ • Normal cells suppress anaerobic glycolysis • Prefer aerobic respiration • Saves glucose
Crabtree effect	In presence of O₂ + too much glucose • TCA cycle activity ↓↓ • Pyruvate → Lactate • Latic acidosis
Rapaport-Leubering Shunt	Occurs only in RBCs Glucose ⇒ ↳ 90%: normal glycolysis = + 2 ATP/glucose ↳ 10%: enters RL shunt • To generate 2,3-Bisphosphoglycerate (2,3-BPG) • No ATP produced • Skips Phosphoglycerate kinase step ↳ (normally produces ATP)
Warburg Effect	Normal Cells • Aerobic Oxidation • Use PKM1 (high activity) • Pyruvate → TCA cycle = 32 ATP Metabolic Reprogramming in Cancer Cells • Use PKM2 (low activity) • Pyruvate → Lactate = 2 ATP ↳ even with O₂ → referred as Aerobic glycolysis • High glucose demand & consumption ↳ Glucose hunger ↳ Cachexia - mediators TNF-a, interleukin-1 ß, and interleukin-6. Function • Generates metabolic intermediates ↳ pyruvate/lactate • for cell growth/division Principle for • 18-FDG (Fluorodeoxy glucose) PET scans  • detects metastasis via increased glucose uptake
Van der bergh's reaction	• Direct positive ⇒ Obstructive jaundice