Lecture 5 GiM

Question 1

What are the factors that lead to cancer?

Answer 1

Various gene and environment factors.

Question 2

What is two-hit hypothesis?

Answer 2

Knudson suggested that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two “hits” had to take place before a tumor could develop, explaining the age difference.

Question 3

What is penetrance?

Answer 3

• Percentage with a gene change who develop the condition
• May be modified by other genetic variations
• May be modified by environmental factors

Question 4

What is the function of gatekeepers gene?

Answer 4

monitor and control cell division and death, preventing accumulation of mutations
directly regulate tumour growth

Question 5

What is the function of caretakers gene?

Answer 5

Improve genomic stability eg repair of mutations

Question 6

What is the function of landscapers gene?

Answer 6

Control the surrounding stromal environment

Question 7

What is the function of tumour suppressor genes?

Answer 7

• Protect cells from becoming cancerous

- Loss of function increase the risk of cancer

Question 8

What is the function of oncogenes?

Answer 8

-Regulate cell growth and differentiation

Question 9

What is oncogenes?

Answer 9

A gene that has potential to cause cancer

Question 10

What is the function of oncogenes?

Answer 10

Regulate cell growth and differentiation

Question 11

What are the examples of tumour suppressor genes?

Answer 11

APC, BRCA1/2, TP53, Rb

Question 12

What are the examples of oncogenes?

Answer 12

Growth and signal transduction factors, RET gene

Question 13

What is the type of inheritance for the most of cancer syndromes?

Answer 13

Autosomal dominant

Question 14

What are the examples of cancer syndromes with autosomal recessive disorder?

Answer 14

MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia

Question 15

What are the characteristics of cancer syndromes with autosomal recessive disorder?

Answer 15

Each parent is a carrier of one faulty copy, usually without the disease
¼ of children inherit both mutated copies and the cancer risk
Appears to skip generations and may account for some sporadic cases

Question 16

What are the ways to find familial cancer genes?

Answer 16

• Disease-causing translocations may give locations of the gene
• Family studies (linkage analysis)
• Candidate gene analysis
• New technologies e.g. whole exome sequencing

Question 17

What are the differences between Sporadic vs Familial cancer?

Answer 17

Sporadic 
-Onset at older age
One cancer in individual
Unaffected family members
Cancers that are rarely genetic e.g. Cervix, lung

Familial
Onset at younger age
Multiple primaries in individual
Other family members affected
Same type/genetically-related cancers

Question 18

Why diagnostic testing are performed?

Answer 18

Initial diagnostic testing (mutational analysis) usually performed on DNA from a relative affected with cancer to try to identify the familial mutation

Question 19

If a mutation is identified in a family, what is the next step that should be taken?

Answer 19

If a mutation is identified in the family, predictive testing for the specific mutation may then be offered to other relatives to determine whether or not they are at risk

Question 20

What are the characteristics of Retinoblastoma condition?

Answer 20

Childhood ocular cancer
Very rare: 1 in 15,000-30000 live births
~30-50 children/year in UK
Classic example following Knudson 2-hit hypothesis
Retinoblastoma (Rb1) gene

Question 21

What are the general information of Retinoblastoma genetically?

Answer 21

Both genes mutated/lost in the tumour
Genetic cases – one mutation is present in germline
Inherited cases occur at younger average age
Bilateral cases almost always germline
15% of apparently sporadic unilateral cases are germline (high new mutation rate)
Other cancer risks e.g. osteosarcoma
Early screening for children at risk

Question 22

What are the characteristics of Familial Adenomatous Polyposis(FAP) ?

Answer 22

Hundreds of bowel polyps (adenomas) from teens onwards
Accounts for ~1% of bowel cancers
High risk (up to 100%) of bowel cancer if untreated
Other features – CHRPE, desmoid tumours, osteomas
APC tumour suppressor gene
Autosomal dominant inheritance
Colonoscopies, total colectomy late teens/early 20s

Question 23

What are the characteristics of Hereditary Non-Polyposis Colorectal Cancer?

Answer 23

Accounts for ~2-3% of bowel cancers

Polyps are common, but not polyposis

60-80% risk of bowel adenomas or cancer from ~mid 20s onwards

Other cancer risks e.g. endometrial/ovarian/stomach/GU

Mismatch repair genes

MLH1 (50%), MSH2 (40%), MSH6 (10%), PMS1/2 (rare)

Autosomal dominant inheritance

Question 24

What is the Amsterdam Criteria?

Answer 24

The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families which are likely to have Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC)

Question 25

What are the benefits of colonoscopic screening in HNPCC?

Answer 25

Patients with HNPCC should have colonoscopy ~every 18-24 months from age ~25
Removal of polyps/early detection of cancer improves survival
?Role of aspirin in preventing polyps

Question 26

What is the percentage of people with breast cancer has mutation of BRCA1/2 genes?

Answer 26

~10% of cases of breast cancer under 40 and ~25% of those with strong FH

Question 27

What are the characteristics of BRCA1/2 genes mutation?

Answer 27

Common mutations in Jewish and some other founder populations
Autosomal dominant inheritance
Risk of breast cancer 80%; ovarian BRCA1 – 40%; BRCA2 – 10-20%
Some increased risk of other cancers – e.g. prostate, melanoma, male breast cancer

Question 28

What are the options for BRCA1/2 gene carriers?

Answer 28

Breast screening – annual MRI 30-50, annual + mammography from ~35-40
Risk-reducing mastectomies +/- reconstruction
Risk-reducing BSO (ovarian screening probably no use)
Lifestyle changes
Pharmacological prevention studies

Question 29

What are the characteristics of Li Fraumeni syndrome?

Answer 29

P53 mutations. Rare
Autosomal dominant
50% risk of cancer by age 40, close to 100% lifetime
Breast, sarcoma, brain, adrenocortical, leukaemia
Avoid radiotherapy – risk of inducing cancers
Limited screening - ?MRI for breast
Poor prognosis
Value of genetic testing less clear