NEOPLASIA2

 Factors that influence the incidence of cancer: Incidence may be related to

 Genetic polymorphism:
 Individual predisposition to disease
 Individual response to environmental agents
 Individual response to drugs (P450)
 Ethnic Factors
 Geographic & environment & other factors (Multifactorial)
 Prostatic & Colorectal & Breast CA: High in USA
 Gastric CA: High in Japan
 Skin CA: High in New Zealand
 Hepatocellular CA: High in Africa & China
 Nasopharyngeal CA: Far East
 Burkitt Lymphoma: Africa
 Environment: "‫"جدول عن اخر موضوع بالصفحة الثانية‬
 Diet: ↑ consumption of fibers + ↓ fat in diet → ↓risk of developing colorectal cancer
 Obesity/Overweight:
 Accumulation of some hormones (estrogen in fats)
 unopposed estrogen (++) → cancers (breast & endometrium)

 Occupation:

 Sunlight: Associated with skin CAs (SCC, BCC, melanoma) & More commonly in fair-skin people
 Personal habits:
 Smoking: lung & nasopharyngeal CA.
 Alcohol: Alcoholic hepatitis, liver cirrhosis

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 Age:
 In general, cancer incidence ≈ AGE n However, certain cancers occur more in children:
 Acute Leukemia & Some Lymphomas
 Some CNS Tumors & Blastomas
 Bone & soft tissue Sarcomas
 Heredity (5% of cancers are familial):
 AD:
 CDKN2A: melanoma
 APC gene: Familial Adenomatous Polyposis Coli
 MEN1 & RET genes: Multiple endocrine neoplasia (MEN syndromes)
 NF1 & NF2 genes: Neurofibromatosis 1&2
 BRCA 1 &2: breast & ovarian cancers
 RB gene: Retinoblastoma
 MSH2, MLH1, MSH6: Hereditary non-polyposis colon cancer
 PTCH1: Nevoid basal cell carcinoma
 TP53: Li-Fraumeni Syndrome
 AR syndromes of Defective DNA Repair: neurofibromas & some skin
pigmentations (Café au lait spots).
 Chromosomal & DNA instability
 Example:
 Nucleotide excision repair genes:
XERODERMA PIGMENTOSUM (BEST EXAMPLE)
 ATM: Ataxia telangiectasia
 BLM: Bloom syndrome
 Genes involved in REPIR of DNA cross links: Fanconi anemia
 Familial cancers with no specific phenotype & multifactorial:
 Family members have higher incidence to common cancers: COLON & BREAST & OVARY CA
 Younger age groups, multiple or bilateral, two or more family members are affected.
 Some linked to inheritance of mutant genes (BRCA-1 & BRCA-2) (AD)
 Acquired Predisposing Conditions:
 Precursor lesions:
 Squamous metaplasia/dysplasia of bronchial epithelium & lung squamous cell Ca.
 Endometrial Hyperplasia & Ca.
 Leukoplakia (Dysplasia) of the cervix, vulva, penis or oral cavity & associated SCC.
 Villous Adenoma (benign in glandular epithelium of colon) & Colorectal Ca
 Immunodeficiency states: virus-related CA (HPV → cervical dysplasia & SCC)
 Chronic inflammation
 Inflammatory bowel diseases: Colorectal CA & Pancreatitis: pancreatic CA
 Gastritis: gastric adenocarcinoma & MALT lymphoma & Chronic cervicitis: cervical CA
 Hepatitis: hepatocellular CA

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 CARCINOGENESIS: MOLECULAR BASIS OF CANCER
 Intro:
 Neoplasms arising from a single clone of cells: MONOCLONAL proliferation
 CLONE:
 A Cell, Cell product that is genetically identical to the unit from which it was derived.
 A population of identical units, cells, or individuals that derive from the same ancestral line.
 Principles:
 Tumors arise from clonal growth of transformed cells that have developed mutations in
several classes of genes:
 Growth promoting proto-oncogenes
 Growth inhibiting tumor suppressor genes (Regular suppressor (RB) & Guardians (TP53))
 Genes regulating apoptosis
 Genes involved in DNA repair
 More than one mutation in above result in abnormal growth of cells

 Genetic Lesions in Tumors:

 Different Gene Lesions:
 Point mutation: Change in a single base in a nucleotide sequence
 may activate an oncogene, or inactivate a tumor suppressor gene (TP53)
 RAS oncogene (codon 12, 13) in Pancreatic carcinoma & subset of colorectal carcinoma
 Translocation:
 A gene rearrangement /movement of genetic materials (from one chromosome to another)
 seen in some solid tumors: Ewing Sarcoma t.(11;22) (q24;q12)
 mainly in lymphoid & hematopoietic tumors:
 Burkitt Lymphoma: 8;14
 Follicular B Cell Lymphoma: 14;18
 Chronic myeloid leukemia (CML): 9;22 (PHILADELPHIA Chromosome)
 Fusion Gene is produced: BCR-ABL (tyrosine kinase activity)
 Gene amplification:
 Double minutes: Small fragments of extrachromosomal DNA
 Homogenous staining regions produced by chromosomal segments with various lengths
&uniform staining intensity
 Examples:
 Neuroblastoma: N-MYC
 Breast carcinoma: HER2/Neu (important for targeted Ab therapy)
 Chromosomal deletions:
 More commonly seen in non-hematopoietic & solid tumors
 EX: Retinoblastoma RB gene 13q14, TP53 gene 17q also several in colorectal CA
 Chromosomes loss or gain: Change from the normal multiples of 23 (Aneuploidy)

There are two types of mutations:

 Driver mutations:
 Alter the function of CA genes
 directly contribute CA development
 and those that do not are termed passenger mutations (acquired mutations)
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  Micro RNAs:
 Non-coding Single stranded RNA of about 22 nucleotides act as regulators of genes
 Overexpression of miRNAs → ↓ the expression of tumor suppressors → carcinogenesis
 Deletion or loss of expression of miRNAs → overexpression of proto-oncogenes.
 Epigenetic changes: Reversible, heritable changes that occur without mutation
Through methylation → may silence tumor suppressor genes & repair genes → carcinogenesis

 Carcinogenesis is a MULTISTEP PROCESS

 Accumulation of mutations of different genes that may come from different gene groups.
 Ex: adenoma → carcinoma sequence in the colon:
 FIRST HIT: NL mucosa undergoes a mutation (activation mutation in one allele of APC gene)
 2nd HIT:
 Inactivation mutation: in another allele of the same gene
 Other gene abnormalities: in other genes (B-catenin), which makes the mucosa at risk
 Activation mutation in oncogenes: K-RAS → mucosa at greater risk of transforming
 Inactivation mutation of p53 → formation of adenoma
 further mutations → Low-grade → High-grade dysplasia in adenoma
 further mutations (telomerase) & gross chromosomal alterations → carcinoma
 transformation of nevi → melanoma.
 Usually benign don’t transform → malignant neoplasms, but this rule has some exceptions

 Tumor Progression:
 Stepwise accumulation of mutations resulting in ↑ features of malignancy:
 More aggressive & Less responsive to therapy

 Heterogeneous Cancer: tumor cells develop mutations different that the other groups in the same
tumor (differences between cancer cells within a single tumor)

 Hallmarks of Cancer:
 Self-sufficiency in growth signals
 Evasion of apoptosis
 Limitless replicative potential (Immortality)
 Ability to invade & metastasize
 Deregulating cellular energetics
 Insensitivity to growth-inhibitory signals
 Altered cellular metabolism
 Evasion of immune surveillance
 Sustained angiogenesis
 Tumor promoting Inflammation

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 GENES IN NEOPLASTIC TRANSFORMATION:
 Genes coding for growth: Classified by site of action
 Proto-oncogenes: NL. /Oncogenes: Mutant/overexpressed proto-oncogenes → Oncoproteins
 They include genes coding:
 GFs  Cell surface receptors
 Cell cycle proteins  Signal transduction proteins
 Inhibitors of apoptosis  Nuclear transcription factors
 Oncogenes coding Growth Factors:
 Cell growth is stimulated by its own GF (autocrine) or other cell (paracrine -from stromal cells)
 Platelet derived growth factor (PDGF) seen in glioblastomas
 Transforming Growth Factor (TGF-a) in sarcomas
 Products of other oncogenes (RAS) may cause overexpression of GF
 Oncogenes coding Growth Factor Receptors:
 GF integrates with membrane receptor that have tyrosine kinase (TK) activity → nucleus
 Mutant receptor → continuous signals even in the absence of GF
 Normal but overexpressed → hypersensitive to GF
 Epidermal GF receptor family:
 ERBB1 in 80% of squamous cell carcinoma of the lung & 50% of GBM
 ERBB2 (HER 2 NEU) in 20% of breast CA, less in adenocarcinomas of lung, ovary,
stomach, and salivary glands
 Increase = POOR PROGNOSIS, presence of these Rs help in giving immune-targeted
therapy (breast CA: treating the HER 2 NEU if it was in the tumor cells)
 Oncogenes in signal transduction:
 RAS action: RAS oncogene
 Commonest oncogene mutation
 present in over 30% of CAs (pancreas & Colon)
 Point mutations in codon 12, 13 are present
 Active (+) RAS → Signal transduction (RAF/MAP-K or
PI3-K/AKT pathways) → transcription activation
 + RAS (GTP) -- GTPase activity by (GAP) →Inactive (GDP)
 Mutations in GAPs (NF1): Neurofibromatosis 1
 Action of ABL:
 Non-receptor associated TK signal transmission
 NL ABL is located in nucleus (promotes apoptosis)
 CML: 9;22 translocation →BCR-ABL hybrid gene
 This new gene protein is retained in the cytoplasm
where it has tyrosine kinase activity
 activates all of the signals downstream of RAS → cell proliferation
 New action is Proliferation + No Apoptosis

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 Nuclear Transcription Factors:
 DNA transcription regulated by genes :MYC*, JUN, FOS
 In normal: MYC protein + DNA → Activation of Cyclin Dependent Kinases (CDKs)
 Initiation of cell cycle → ↓ MYC
 MYC mutation → sustained activation
 Examples:
 Dysregulation of MYC in Burkitt lymphoma due to translocation t (8;14)
 MYC amp. in Breast, colon, lung CA.
 NMYC amp. in neuroblastoma
 Cyclins & Cyclin Dependant – Kinases regulate cell cycle phases
 Family of proteins that control entry of the cells at specific phases of cell cycle (D, E, A, B)
 Level of a specific cyclin ↑ at a specific phase & ↓ rapidly after the cell departs that phase
 Function by phosphorylating certain proteins (RB protein)
 Cyclins bind to CDKs, activating them
 Two important checkpoints:
 Cyclin D family → CDK4 & CDK6 at G1 → S phase
 Cyclin B-CDK1 activate G2 → M transition
 Activity of CDK/ Cyclin is regulated by CDK inhibitors (Selective or nonselective inhibition)
 Examples: p21, p27 & p57 inhibit all CDKs
 INK4 Inhibitors (p15, p16, p18 & p19) inhibit CDK4 & CDK6
 Expression of p21 is controlled by the tumor suppressor protein p53 → G1 phase arrest
 Mutations that dysregulate activity of cyclins & CDKs → cell proliferation
 Cyclin D is overexpressed in breast, liver & esophageal cancers
 Amplification of CDK4 gene is present in melanomas, sarcomas & glioblastoma
 Disabling mutations of CDKN2A (encoding p16): germline (melanoma-prone kindreds)
or acquired (pancreas /esophagus Ca, GBM)

 Cancer Suppressor Genes:

 Growth inhibitory pathway by:
 Regulate cell cycle: RB gene
 Regulate cycle & apoptosis: TP53
 Block GF signals: TGF-b
 APC regulates b-catenin
 Cancer suppressor genes are recessive genes which may be lost in familial or sporadic cases.
 In cases with familial predisposition for development of tumors, affected persons inherit:
 one defective (nonfunctional) copy of a tumor suppressor gene
 lose the second one through somatic mutation.
 In sporadic cases, both copies are lost through somatic mutations.

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 RB gene (Governor of cell cycle):
 First studied in Retinoblastoma (RB gene → RB protein)
 Both copies of gene must be lost for neoplastic transformation to occur (loss of heterozygosity)
 Familial (RB → RB) or Sporadic (RB → RB → RB)
 Mode of action of RB gene:
 G1→ S requires the activity of cyclin E/CDK2
 Cyclin E is dependent on the E2F family of transcription factors (TFs)
 Active hypophosphorylated RB binds to & inhibits the E2F→ no transcription of cyclin E
 GF signaling leads to cyclin D expression & activation of cyclin D-CDK4/6 complexes
 phosphorylate RB, inactivating the protein & releasing E2F → TRANSCRIPTION (G1 → S)
 Many oncogenic DNA viruses (HPV) encode proteins (E7) → bind to RB & render it non-functional
 Retinoblastoma:
 Sporadic in 60% of cases, Familial (40%)
 In familial form, patients carry one mutation → followed by 2nd mutation in retinal cells
 No tumor develops unless two alleles in chr. 13q14 become mutant (two hit theory)
 Familial form: ↑ incidence of bilateral (osteosarcoma & other tumors)
 TP53 (Guardian of Genome):
 The most commonly mutated gene (and suppressor gene) in human CA
 homozygous loss in 70% of CA
 TP53 is a negative regulator of cell cycle (protein product is p53)
 (Guardian/Policeman): preventing genetically damaged cells from progressing through new cycle.
 p53 is inactivated by its negative regulator MDM2.
 DNA damage / other stresses will lead to the dissociation of the p53 and MDM2 complex.
 Mode of activation & action:
 p53 senses DNA damage /other stresses through sensors: protein kinases
(Ataxia telangiectasia mutated (ATM) protein)
 p53 released from MDM2 & activated with longer half-life
 Transcription of CDKI gene CDKN1A (p21) → cell cycle arrest at G1 (Quiescence)
 Result: more time for repair → Normal
 If repair fails:
 Senescence (permanent cell cycle arrest)
 Apoptosis
 Fixed mutation = NEOPLASIA
 More functions of TP53:
 Transcription of certain repair genes, micro RNAs (inhibit cyclins and BCL2)
 positive regulator of apoptosis (BAX & PUMA).
 Significance of TP53 mutation:
 Acquired mutation in many cancers (colon, breast, lung, leukemia)
 Inherited mutation in one allele: Li-Fraumeni syndrome → 25 fold ↑ malignancy:
sarcoma, leukemia, breast carcinoma and gliomas
 May be blocked by some DNA viruses (oncogenic HPV, HBV, EBV & others) producing
viral-induced cancers

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