Cancer 3) Biology of cancer

Question 1

What has studying retinoblastoma illustrated?

Answer 1

Tumour suppressor genes and hereditary cancer

Question 2

What has studying breast cancer illustrated?

Answer 2

Genetic risk
Screening
Synthetic lethality

Question 3

What has studying CML illustrated?

Answer 3

Oncogenes
Philadelphia chromosomes
Targeted therapy

Question 4

What is the evidence that cancers are clonal?

Answer 4

Derived from single cell of origin (all carry same founding mutation e.g. Philadelphia mutation in CML)
Increasingly malignant sub-clones emerge through process of Darwinian selection
Evidence in women: all cells in a cancer exhibit lyonisation of same X chromosome
Transplantation studies of cancer cells in animals provide evidence for cancer stem cells that can reproduce cancer

Question 5

What does multiple myeloma exhibit that gives evidence that cancers are clonal?

Answer 5

Monoclonal immunoglobulins on serum protein electrophoresis

Light chain restriction

Question 6

What is a mutation?

Answer 6

Structural change in DNA that can be transmitted to daughter cells

Question 7

What are somatic and germline mutations?

Answer 7

Somatic - present in proportion of cells. Not transmitted to offspring
Germline - present in gametes and every cell of offspring

Question 8

What are the multiple causative factors that may cause cancer?

Answer 8

Environment - diet, lifestyle
infection
Genetic

Question 9

What is retinoblastoma?

Answer 9

Rare childhood cancer. Tumour caused by mutations in Rb tumour suppressor gene

Question 10

What are the 2 types of retinoblastoma?

Answer 10

Familial form (40%) - child inherits germline copy of mutant Rb gene. Occur at young age, bilateral and multifocal
Sporadic form (60%) - spontaneous mutations of both copies of Rb gene must occur in same retinal cell for tumour to occur. Unilateral

Question 11

What does the retinoblastoma protein pRb do?

Answer 11

Holds cells in G0 preventing progression to S phase
Regulates cell cycle progression
Inhibits transcription of cell cycle proteins by binding to transcription factor E2F

Question 12

What is the consequence of absent functional pRb?

Answer 12

DNA replication occurs in presence of damaged DNA
Increased replication rates
Predisposes to further mutations

Question 13

Describe BRCA1

Answer 13

Large nuclear protein
Cell cycle checkpoint signaller
Transcriptional regulation
Involved in repair of DNA double-stranded breaks

Question 14

Describe BRCA2

Answer 14

Large nuclear protein. Involved in repair of DNA double-stranded breaks

Question 15

How is breast cancer risk calculated?

Answer 15

Using risk estimate models

Based on age, family history and personal risk factors

Question 16

Describe the low risk of breast cancer group and the recommendations

Answer 16

Population risk
Less than 3% risk aged 40-50yo
Lifetime risk below 17%
Mammography screening from 50yo

Question 17

Describe the moderate risk breast cancer group and recommendations given

Answer 17

3-8% risk aged 40-50yo
Lifetime risk 17-30%
Below 40yo - information, counselling
40-49yo - annual mammography

Question 18

Describe the high risk breast cancer group and recommendations given

Answer 18

Above 8% risk between 40-50yo
Lifetime risk above 30%
Refer to specialist clinic, genetic counselling
Genetic testing if affected family member

Question 19

What factors in the family history make someone high risk for breast cancer?

Answer 19

2 relatives with breast cancer below 50yo
3 relatives with breast cancer below 60yo
4 relatives with breast cancer at any age
Ovarian cancer + breast cancer below 50yo
Bilateral breast cancer below 50
Male breast cancer + breast cancer below 50yo
Jewish ancestry
Multiple cancers at young age

Question 20

How can we reduce the risk of breast cancer?

Answer 20

Prophylactic treatment 
 - surgical: breasts, ovaries
 - medical: tamoxifen
Surveillance
 - mammography, MRI
 - CA-125
 - ultrasound pelvis

Question 21

How is cisplatin useful in breast cancer?

Answer 21

BRCA1 and BRCA2 deficient tumours should be more sensitive as cisplatin induces DNA damage that is normally repaired by BRCA1 and BRCA2