Tumor pathology 5 MW +

Question 1

Disruption of normal regulatory genes

Answer 1

–Tumour-suppressor genes (anti-oncogenes)

•Normal growth-inhibiting genes

–Genes negatively regulating mitosis - Rb

–Genes regulating APOPTOSIS

–Genes regulating DNA repair

–PROTO-ONCOGENES

•Normal genes that promote normal cell growth and mitosis

Question 2

What is the key event in tumour formation

Answer 2

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

Question 3

Retinoblastoma gene: an anti-oncogene

Answer 3

• 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]

Question 4

Sporadic vs inherited retinoblastomas

Answer 4

•“TWO-HIT HYPOTHESIS” of oncogenesis

–INHERITED FORM

• one defective inherited copy of pRb
• somatic point mutation of other copy

–SPORADIC FORM

•both hits occur in a single cell

loss/inactivation of both normal

allelic copies gives rise to cancer

Question 5

Carcinogenesis

Answer 5

•Heredity

–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.

Question 6

Inherited predisposition to cancer

Answer 6

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

Question 7

Proto-oncogenes

Answer 7

•Normal genes coding for normal proteins that regulate growth

–Growth factors

–Growth factor receptors

–Signal transduction

Question 8

ONCOGENES
Cancer-causing genes

Answer 8

• Derived from proto-oncogenes

Activated by:

• Alteration of proto-oncogene structure
• point mutation
• chromosome rearrangements + translocations
• Dysregulation of proto-oncogene expression
• gene amplification
• overexpression

Question 9

Oncogenes generate active ONCOPROTEIN products e.g?

Answer 9

–Growth Factors

–Growth Factor Receptors

–Proteins involved in Signal Transduction

–Nuclear Regulatory Proteins

–Cell Cycle Regulators

Question 10

Viral carcinogenesis:
More than one mechanism

Answer 10

• 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)

•

Question 11

Chemical carcinogenesis

Answer 11

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

Question 12

Multistep caricnogenesis

Answer 12

• 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

Question 13

Diagram

Answer 13