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Molecular Basis Of Cancer

  1. Nonlethal genetic damage which can be inherited & Acquired (N) Regulatory genes:
  2. P- Oncogenes → Growth promoting → Dominant
  3. Anti-Oncogenes → Growth inhibitory, cancer suppressor Recessive
  4. Apoptosis gene                 
    1. May be Dominant / Recessive
    2. They are also known as Genes for DNA repair                        
    3. Carcinogenesis is a Multi step process         
    4. Proto oncogene were first discovered by Varmus and Bisho, tumour progression is the main mechanism seen when apoptosis gene stop there regulation  .
    5. Three types of cells seen in human body  
      1. Continuously dividing cells/ Labile cells
        1. Epidermis,   
        2. bone marrow cells
      2. Quiescent/Stable cells
        1. ­Stable cells      
        2. Hepatocytes                
      3. Non-dividing / permanent cells
        1. Kidney cells,                                     
        2. Mesenchyme                        
        3. Fibroblast & smooth muscles cells            
        4. Neurons
        5. Cardiac myocytes                            
        6. Striated muscle (some activity from Satellite cells) 
  5. Protooncogene: QQ
    1. Main mechanism is binding of growth factor to receptor
    2. Transient and limited activation of the growth factor receptor causes activation of signal transducing proteins which lead to Transmission of signal to nucleus ultimately leading to Activation of nuclear regulatory factors 
  6. Oncogenes: Q
    1. Derived from proto-oncogenes, which promote normal growth & differentiation.
    2. Discovered in acute-transforming retrovirus by Varmus & Bishop
    3. Many proto-oncogenes named after viral homo logus


Figure - Subcellular localization and functions of major classes of cancer-associated genes. 

  1. Encode proteins- Onco proteins:
    1. Devoid of regulatory elements     
    2. Their production doesn't depend on growth factors or other external signals

Ras Q Attached to Cell membrane by farnesyl anchor   

  1. Inactive ras - GDP bound
  2. 10-20% of Human tumors contain mutated ras
  3. Most common abnormality in dominant oncogenes in humans
  4. Active ras - GTP bound
  5. On activation by Growthfactor Inactive –form is converted to Active ras signal transduction
  6. GAP'S (encoded by NF1gene). Mutation of Neurofibromin → (NF-l) 
  7. GTP-ase activating protein → Neoplasia 

Ras genes: Q mainly of three types namely

  1. N - ras - Hematopoietic tumors (AML), Melanomas
  2. K-ras - Carcinoma colon, lung, pancreas
  3. H-ras - Bladder and kidney tumors
  1. Features of Ras genes:
    1. In cell cycle in G1 -S phase: ras controls CDK levels
    2. To block ras activity, inhibit farnesyl transferase (causes ca). 
  2. Non receptor associated tyrosine kinase Q
    In humans:
    c-abl (chromosome - 9)     
    c-abl : has tyrosine kinase activity
    : Inhibited by negative regulatory domains



Table: Selected oncogenes, their mode of activation, and associated human tumors

Category Growth factors


Mode of activation

Associated human tumor

PDGF-β Chain






Fibroblast growth factors






Stomach cancer

Bladder cancer

Breast cancer












Thyroid cancer

Growth factors receptor




EGF receptor family





Squamous cell carcinoma of lung.

gliomas breast and ovarian


CSF -1 receptor


Point mutation


Receptor for neurotrophic




Point mutation


Multiple endocrine neoplasia 2 A

and B, familial medulary

thyroid carcinomas

PDGF receptor




Receptor for stem cell

( steel )factor


Point mutation

Gastrointestinal stromal tumors

and other soft tissue tumors


Proteins involved in signal Transduction

GTP - binding



Point mutation


Colon, lung, and pancreatic




Point mutation

Bladder and kidney tumors



Point mutation

Melanomas , hematologic


Non receptor tyrosine




Chronic myeloid leukemia

Acute lymphoblastic leukemia

RA S signal transduction


Point mutation


WNT signal transduction

β catenin


Hepatoblastomas, hepatocellulor


Nuclear regulatory





Transcriptional activators


Point mutation

Burkitt lymphoma




Neuroblastoma, small cell

carcinoma of lung




Small cell carcinoma of lung

Cell cycle regulators







Mantle cell lymphoma




Breast and esophageal cancer




Breast cancer

Cyclin-dependent kinase



Amplification or

Point mution

Glioblastoma, melanoma, sarcoma


Nuclear transcription proteins: All signal transduction pathways enter nucleus

Regulated by family of genes products of which control transcription of growth related genes e.g.: myc, myb, jun, fos c-myc; Q- expressed in virtually all eukaryotic cells belongs to immediate early growth response genes

-Myc activation in absence of survival signals Apoptosis (conflict Model)

-Burkitt's lymphoma: t (8 ; 14) Q

Chromosome 8: c-myc

Chromosome 14: IgH locus

Cancer Surrpressor Genes

Apply brakes to cell proliferation
Rb gene
i.     First tumor suppressor gene to be discovered
ii.    Most common studied: Rb gene: Chromosome 13 q 14
iii.   Expressed in every cell type examined
iv.   pRb serves as brake on advancement of cell from Gl to S
v.    Mutations of Rb gene - in 'Rb pocket'
vi.   Retino blastoma - 6% Sporadic, 40% familial
Knudson's "two-hit- hypothesis      
  1. In hereditary cases - Ist hit is inherited (present in all somatic cells)
  2. IInd hit occurs in one of many retinal cells
  3. In sporadic cases - both hits occur somatically in a single retinal cell
  4. Recessive cancer gene: When both (n) copies are lost, retinoblastoma is produced
Table: Main tumor supressor genes.
Subcellular Location Gene Function Tumors Associated with Somatic Mutations Tumors Associated with Inherited Mutations
Cell surface TGF-βreceptor

Growth inhibition
Cell adhesion
Carcinomas of colon

Carcinoma of stomach

Familial gastric cancer
Inner aspect of plasma membrane NF-1 Inhibition of RAS signal transduction and of p21 cell-cycle inhibitor Neuroblastomas Neurofibromatosis type 1 and sarcomas
Cytoskeleton NF-2 Cytoskeletal stability Schwannomas and meningiomas Neurofibromatosis type 2, acoustic schwannomas and meningiomas
Cytosol APC/ β-catenin Inhibition of signal transduction Carcinomas of stomach, colon, pancreas; melanoma Familial adenomatous polyposis coli/colon cancer
  PTEN PI-3 kinase signal transduction Endometrial and prostate cancers Cowden syndrome
  SMAD 2 and SMAD 4 TGF-βsignal transduction Colon, pancreas tumors Unknown
Nucleus RB Regulation of cell cycle Retinoblastoma; osteosarcoma ca of breast, colon, lung Retinoblastomas, osteosarcoma
  p53 Cell-cycle arrest and apoptosis in response to DNA damage Most human cancers Li-Fraumeni syndrome; multiple carcinomas and sarcomas
  WT-1 (INK4a)
Nuclear transcription
Regulation of cell cycle by inhibition of cyclin-dependent kinases
Wilms tumor
Pancreatic, breast, and esophageal cancers
Wilms tumor
Malignant melanoma
  BRCA-1 and BRCA-2 DNA repair Unknown Carcinomas of female breast and ovary; carcinomas of male breast
  KLF6 Transcription factor Prostate Unknown
  1. P 53 geneQ:
  1. Located on Chromosome 17 β 13.1
  2. Single most common target for genetic alteration in humans (Present in > 50% human tumors) Q
  3. One inherited mutant gene:
  4. Li Fraumeni syndrome Q 25-fold greater chance of developing malignancy (by 50 years of age):
  5. Younger age, multiple primary tumor
  6. Critical Gatekeeper /Molecular policeman / Guardian of genome
  7. Localized to nucleus Q        
  8. Short   t 1/2   20 min.
  • Doesn't police normal cell cycle (unlike Rb), for emergency brakes only
  • Most common mutation: DNA binding domain
  • Down regulation of p53 is by MDM-2 (Oncogene)
  • E6 protein of HPV- binds and degrades P53

Fig: The role of p53 in maintaining the integrity of the genome

-  is known as  big brother of p53
-   present on chromosome 1p36
-   is very similar to p53:action is cell cycle arrest & apoptosis

Deletions: causes Neuroblastoma colon, & breast cancer Q
Signal Transduction
  1. APC: Chromosome 5q21 Q      
    Familial Polyposis syndromes:
    a. Gardner syndrome   
    b. Turcot syndrome         
    c. HNPCC  
    d. P/J syndrome
  2. FAP: archetype of APC:
    a. 500-2500 colonic adenoma (min. 100)    
    b. Prophylactic colectomy
  3. Gardner syndrome- AD intestinal polyps multiple osteomas (of mandible, skull, long bones) Q
  • Epid. Cysts, fibromatosis
  • Abnormality of dentition
  • ↑ Frequency of duodenum & thyroid Ca
  1. Turcot Syndrome: Intestinal polyps with CNS tumor (Gliomas)
    • Polyposis at teens twenties, Ca within 10-15 years
  2. HNPCC/Lynch syndrome: AD Q
  • Not ass. with APC pre-existing adenomas
  • ↑ risk of intestinal & extra-intestinal Ca (endometrial Ca)
  • defect in mismatch repair genes
  1. NF-l gene:
Neurofibromatosis Type I
  • AD, 1 in 3000
  • Chromosome: 17 q 11 - Neurofibromin (GTPase activating protein)
Clinical feature:
  1. Solitary & plexiform NF, glioma of Optic nerve;
  2. pigmented iris nodules (Lisch nodules); Cutaneous hyperpigmented spots (cafe au lait) (> 6, >1.5 cm) more than 6; >1.5 cm each)
  3. ↑risk of development of - Neurofibrosarcoma (5'%), AML         
NF-2 - Neurofibromatosis Type II
  1. AD. 1 in 40.000
  2. Chromosome 22 q 12 →  Merlin: homologous to RBC membrane cytoskeletal protein
  3. Pathogenesis - Not known
  4. Clinical: B/L acoustic schwannomas, multiple meningiomas, glioma, ependymoma of spinal cord.
Cell Surface Receptors

  1. TGF β binding → up regulation of transc. of growth inhibitor - genes (CDK inhibitor) Others
  2. Cadherins: Glue between epithelial cells
  3.            : ↓ expression in Ca & adenoma
  4. Involved in cell - cell & cell matrix interactions
  5. Assoc. with Colonic Ca
  6. VHL: Chromosome 3p. Assoc. with RCC
  7. PTEN: Phosphatase & Tensin homologen
  8. Chromosome 10q23
  9. Endometrial. Breast Prost. Ca. glioblastoma
  10. WT -1: Chromosome llpl3. Assoc. with wilm’s tumor
  11. Inhibits transcription of growth promoter gene
  12. WT-2 → on chromosome 11 p15, back with Weidman syndrome
Mismatch repair genes –
  1. Act as spell checkers when a strand of DNA is replicating.
  2. Without these, errors slowly    accumulate in several genes (proton cogenes / tumor suppressor genes) → Replication error phenotype(RER).
  3. Replication error phenotype documented by micro satellite instability: Microsatellites are tandem repeats of 1-6 nucleotides scattered through out genome, fixed for an individual, fixed for life.
  4. No pre-existing adenomas
  5. An important example for mismatch genes is  HNPCC (Predominantly caecum & proximal colonic carcinoma­)
  6. Defect in 'Mismatch repair genes'
Nucleotide excision Repair (NER)
  1. U. V. light → Cross linking of pyrimidine residues → Repaired by NER pathway.
  2. Mutations in NER genes - Xeroderma 'pigmentosa
Repair by homologous recombination
  1. Repair double stranded DNA breaks by homologous recombination
  2. Genes involved are →
  1. ATM gene - senses double stranded DNA breaks. ATM mutations - Ataxia Telangiectasia
  2. Mutation in heli case → Blooms syndrome
  3. BRCA1 and BRCA2 → hereditary breast and ovarian cancers not associated with sporadic Cas
  4. BRCA1 - 17q21, High risk of breast and epithelial ovarian Ca, Slightly ↑ risk of prostate & colonic
  5. Age at which cancer appear is 40-50 years       
  6. BRCA2 - 13q12, ↑ Risk of Ca ovary, Ca male breast.
  7.  Age at which Ca appears is 50 years or older.
  8. Participate in repair of double stranded DNA breaks by homologue recombination. 
Table: Inherited predisposition to cancer
1. Inherited Cancer Syndromes (Autosomal Dominant)
Gene Inherited Predisposition
RB Retinoblastoma
p53 Li-Fraumeni syndrome (various tumors)
p16INK4A Melanoma
APC Familial adenomatous polyposis/colon cancer
NF1, NF2 Neurofibromatosis 1 and 2
BRCA1, BRCA2 Breast and ovarian tumors
MEN1, RET Multiple endocrine neoplasia 1 and 2
MSH2, MLH1, MSH6 Hereditary nonpolyposis colon cancer
PTCH Nevoid basal cell carcinoma syndrome
2. Familial Cancers
i. Familial clustering of cases, but role of inherited predisposition not clear for each individual
ii. Breast cancer (not linked to BRCA1 or BRCA2)
iii. Ovarian cancer
iv. Pancreatic cancer
Inherited Autosomal Recessive Syndromes of Defective DNA Repair
i. Xeroderma pigmentosum
ii. Ataxia-telangiectasia
iii. Bloom syndrome
iv. Fanconi anemia

Fig: Flow chart depicting a simplified scheme of the molecular basis of cancer.

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