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Flashcards in Tumor pathology 5 MW + Deck (13)
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Disruption of normal regulatory genes

–Tumour-suppressor genes (anti-oncogenes)

•Normal growth-inhibiting genes

–Genes negatively regulating mitosis - Rb

–Genes regulating APOPTOSIS

–Genes regulating DNA repair


•Normal genes that promote normal cell growth and mitosis



What is the key event in tumour formation

Uncontrolled cell proliferation via cell cycle dysregulation through loss of tumour suppressor gene function


Retinoblastoma gene: an anti-oncogene

Rb gene mutations favour cell proliferation

•Mutations in other genes controlling pRb phosphorylation mimic the effect of pRb loss:

–Mutational activation of cyclin D or CDK4

–Mutational inactivation of CDKIs also drive proliferation


Note: Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissueof the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively found in young children.[1]


                        Sporadic vs inherited retinoblastomas

•“TWO-HIT HYPOTHESIS” of oncogenesis


•one defective inherited copy of pRb

•somatic point mutation of other copy


•both hits occur in a single cell

loss/inactivation of both normal

allelic copies gives rise to cancer




–accounts for 5-10% of all cancers

–Inherited cancer syndromes

–Familial cancers

Autosomal recessive syndromes of defective DNA repair

Note: An autosomal recessive disorder means 2 copies of an abnormal gene must be present in order for the disease or trait to develop.


Inherited predisposition to cancer

Familial cancers

•family clustering of cancers but individual predisposition unclear

multifactorial inheritance

•early age of onset

•multiple / bilateral tumours

-Some Breast cancers

-Some Ovarian cancers

-Non-FAP colon cancers




•Normal genes coding for normal proteins that regulate growth

Growth factors

–Growth factor receptors

–Signal transduction


Cancer-causing genes

•   Derived from proto-oncogenes

Activated by:

• Alteration of proto-oncogene structure

• point mutation

• chromosome rearrangements + translocations

Dysregulation of proto-oncogene expression

• gene amplification



Oncogenes generate active ONCOPROTEIN products e.g?

Growth Factors

–Growth Factor Receptors

–Proteins involved in Signal Transduction

–Nuclear Regulatory Proteins

–Cell Cycle Regulators


Viral carcinogenesis:
More than one mechanism

•virus genome inserts near a host proto-oncogene

•viral promoter or other transcription regulation elements cause proto-oncogene over-expression

Retroviruses  insert an oncogene into host DNA causing cell division

•DNA viruses known to cause cancer in humans

HPV (cervical cancer)

Hepatitis B (liver cancer)

EBV (Burkitt lymphoma)


Chemical carcinogenesis

Adduct formation at particular chromosome sites lead to activation of oncogenes and suppression of anti-oncogenes



Multistep caricnogenesis

•All sporadic cancers harbour multiple genetic aberrations (deviation from norm)

Abnormalities accumulate with time

•Activation of several oncogenes and loss of 2 or more anti-oncogenes occurs in most cancers