T5: Familial Cancer Predisposition

Question 1

What factors lead to cancer development?

Answer 1

• Caretaker genes - such as DNA repair and carcinogen metabolism
• Gatekeeper genes - cell cycle control and programmed cell death genes
• Macro-environment - chemicals, viruses, radiation and physical agents
• Micro-environment - oxygen free radicals, hormones, growth factors etc.

Question 2

What is cancer?

Answer 2

A series of genetic changes occur within cells leading to increasingly abnormal behaviour and histology.

Question 3

What is the Two-Hit Hypothesis?

Answer 3

Knudson’s two hit hypothesis For any individual cell, there is only a problem when both alleles are taken out. In sporadic tumours, there is no genetic predisposition, over time due to exposure one of the allele acquires a mutation. That in itself will not cause too much damage until the other allele is knocked out. It is more likely to happen sooner in familial inheritance, as only one gene needs to be knocked out.

Question 4

What is penetrance?

Answer 4

This is the percentage of a patients with the variety who will develop the condition. It varies with the condition. This can be modified by genetic factors to environmental factors.

Question 5

Give examples of important types of genes involved in the prevention of cancer.

Answer 5

Gatekeepers - directly regulate tumour growth; monitor and control cell division and death, preventing accumulation of mutations.

Carekeepers - improve genomic stability e.g. repair of mutations.

Landscapers - control the surrounding stromal environments.

The more important to gene function, the more drastic the effect if removed.

Tumour suppressor genes - These are cells protective from cancer, loss of function increases the risk of cancer e.g. APC, BRCA1/2, TP53, Rb

Oncogenes - These regulate cell growth and differentiation. A gain of Function/activating mutations increases the risk of cancer e.g. growth and signal transduction factors, RET gene

Question 6

What pattern of inheritance do most cancer syndrome show? Give examples.

Answer 6

Autosomal dominance:

Most cancer syndromes show an autosomal dominant inheritance pattern. The affected person may not have had the gene. The gender of the child can affect penetrance such as in the BRCA1/2 mutation; females are usually affected by ovarian/breast cancer but males can have the change and be passed on (they can also rarely have the cancer).

More rarely there are a few cancer syndromes that show autosomal recessive inheritance pattern e.g. MUTYH associated polyposis, Fanconi anaemia, Ataxia Telangiectasia. Each parent is a carer of one mutated copy, usually without the disease. There is a risk of 1/4 children inherited both mutated copies and the cancer risk. It appears to skip generations and may occur sporadically.

Question 7

What are differences between sporadic and familial cancer?

Answer 7

Sporadic cancer:

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

Familial cancer:

- Onset at a younger age - key red flag 
- Multiple primaries in an individual 
- Other family members are affected 
- Same type/genetically-related cancers through family
- Family history is a key piece of information

Question 8

What are differences between diagnostic and predictive testing?

Answer 8

Initial diagnostic testing (mutational analysis) is usually performed on DNA from a relative affected with cancer to try to identify the familial mutation. Takes about 6 months.
If a mutation is identified in the family, predictive testing for specific mutation may then be offered to other relatives to determine or not they are at risk. Takes 4-6 weeks.

Question 9

Using the example of BRCA1 and 2 genes, how can genes lead to genetic predisposition to cancer?

Answer 9

• BRCA1&2 are involved in DNA repair
• Responsible for ~10% of cases of breast cancer under 40 and ~25% of those with strong family history
• 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

Options for gene carriers include annual breast (age 30-50) screening and mammogram from 40. Also risk reducing mastectomies and reconstructions. Also lifestyle changes.

Question 10

Using the example of Lynch syndrome, how can genes lead to genetic predisposition to cancer?

Answer 10

Lynch Syndrome is HNPCC

• Accounts for ~2-3% of bowel cancers
• Polyps are common
• 60-80% risk of bowel adenomas or cancer from ~mid 20s onwards
• Other cancer risks e.g. endometrial /ovarian /stomach /urinary tract
• Due to error in Mismatch repair genes
• MLH1 (50%), MSH2 (40%), MSH6 (10%), PMS2 (rare)
• Autosomal dominant inheritance

Carriers have a colonoscopy every 18-24 months, removal of polyps and early detection of cancer. Also the use of aspirin in prevention.

Question 11

Using the example of FAP, how can genes lead to genetic predisposition to cancer?

Answer 11

FAP - Familial Adenomatous Polyposis

• Patients have 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 (Congenital hypertrophy of the retinal pigment epithelium), desmoid tumours, osteomas
• APC tumour suppressor gene
• Autosomal dominant inheritance
• Prevention includes colonoscopies, total colectomy late teens/early 20s

Question 12

What pattern of inheritance do genes have at the cellular level?

Answer 12

Autosomal recessive i.e. both copies of the gene must be inactivated to have the effect