Lecture 3

Question 1

Are tumors derived from a single
abnormal cell?

Answer 1

Various observations suggest that this is the case:
1. Karotyping/dna analysis
2. X chromosome inactivation

Question 2

1. Karyotyping/DNA Analysis

Answer 2

Chronic Myelogenous Leukemia (CML)BCR-ABL fusion protein
Philadelphia Chromosome Marker of CML

Question 3

2. X Chromosome inactivation

Answer 3

Patches of cells in adult inherit the pattern of X- inavtivation of their ancestors in the embryo. One cell becomes ancestor of all cells in the tumour

Question 4

Multistep Nature of Cancer

Answer 4

The tendency of untreated tumors to develop from
benign or small to malignant, large tumors over time

Question 5

Do Tumors develop from mildly aberrant cells?

Answer 5

e.g.
Radiation: Leukemia 8 years
Tobacco Smoke: Lung cancers 20 years approx
During “Lag Phase” tumor Cells are undergoing a
succession of changes (multiple genetic/epigenetic
changes)

Question 6

An activating mutation in a single oncogene is not
sufficient to cause cancer

Answer 6

Oncogenes must collaborate with one another
and with inactivation of Tumour Suppressors in
order to generate cancers
* In precancerous and cancerous cells many
chromosomal alterations are seen

Question 7

For most tumours what model best fits the data

Answer 7

For most tumors, it is the cumulative damage model
that best fits the data (Cancer and Age-takes time for
malignant tumours to develop)

Question 8

Towards a model:
an initial description

Answer 8

Tumors arise from a population of abnormal
cells, derived from a single mutant ancestor,
acted upon by mutation and selection

Question 9

Human colon cancer is an excellent example of model

Answer 9

• Small benign tumors (adenomas) in colorectal epithelium
• Adenomas grow/disorganize, acquiring malignant phenotype
  – These alterations
  are correlated with
  a sequence of
  gene changes
  » Inactivation of tumorsuppressor genes AND Activation of oncogene

Question 10

Inherited single gene defects and
Cancer Susceptibility

Answer 10

1. Accounts for 5-10% of all cancers
2. Retinoblastoma, a childhood eye cancer (RB tumour
   suppressor) and Li-Fraumeni syndrome (p53) in which children
   and young adults develop different cancers including brain
   tumors, leukemia breast cancer.
3. BRCA1 and 2-predisposition to breast and ovarian cancer.
   APC (adenomatous polyposis coli) gene mutations have been
   identified as a cause of inherited precancerous polyps, and a
   contributor to colon cancer

Question 11

Familial Cancers as a model to study
T.S. genes
Example: Retinoblastoma

Answer 11

Tumor of the neural precursor cells in retina
RB1 gene on Chromosome 13q14
Two forms: Familial or Sporadic

Question 12

Two forms; Familial and sporadic

Answer 12

Familial (Hereditary): Multiple tumors, affecting both
eyes, early onset, 6x increased cancer risk
Sporadic (Non-hereditary): Single tumor,
affecting one eye, later onset - chromosome 13 with RB locus deleted