L5- Familial Cancer

Question 1

Caretaker genes do what tasks?

Answer 1

DNA repair
Carcinogen metabolism

improve genomic stability e.g. repair of mutations

Cancer e.g: HNPCC

Question 2

Gatekeeper genes do what?

Answer 2

Cell cycle control
Programmed cell death

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

cancer e.g: FAP

Question 3

Macroenvironments involves what?

Answer 3

Chemical
viruses
radiation
physical agents

Question 4

Microenvironments involves what?

Answer 4

Oxyradicals
Hormones
Growth factors

Question 5

What is the two hit hypothesis theory

Answer 5

You need changes in both copies of a gene for cancer to develop. If one of the genes is hit in a germ line mutation , a second somatic one is more likely to occur to enable cancer

Recessive at the cellular level (i.e. both copes of the gene inactivated to have effect).
Autosomal dominant pattern of inheritance of the cancer risk

Question 6

What is cancer

Answer 6

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

Question 7

What is Penetrance?

Answer 7

Percentage with a gene change who develop the condition

• May be modified by other genetic variations
• May be modified by environmental factors

Question 8

Landscapers do what?

Answer 8

Control the surrounding stromal environment

Cancer e.g: JPS, UC

Question 9

What do Tumour Suppressor genes do?

Answer 9

Protects cells from becoming cancerous

• Loss of function increases the risk of cancer
• e.g. APC, BRCA1/2, TP53, Rb

Question 10

What do Oncogenes do?

Answer 10

Regulate cell growth and differentiation

• Gain of function/activating mutations increase the risk of cancer
• e.g. Growth and signal transduction factors, RET gene

Question 11

A few cancer syndromes show autosomal recessive inheritance pattern, which ones?

Answer 11

.MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia

Question 12

Mutation types

Answer 12

Splice site mutations

Large deletions and duplications

Translocations

Question 13

How to find familial cancers?

Answer 13

Disease-causing translocations may give locations

Family studies – linkage analysis

Candidate gene analysis

New technologies e.g. whole exome sequencing

Question 14

What would you include in a family history?

Answer 14

Include maternal and paternal sides

At least 3 generations

Children, siblings, parents, uncles, aunts, nephews, nieces, grandparents, cousins

Types of cancer, age of diagnosis

Confirm if possible – medical records, cancer registries, death certificate

Question 15

Sporadic vs Familial Cancers

Answer 15

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 16

Purpose of genetic assessment

Answer 16

Diagnosis/explanation of family history
Counselling of advantages and disadvantages of testing
Risk of further cancers for affected cases
Risk of cancer for unaffected relatives
Screening
Prevention
Treatment
Research

Question 17

Diagnostic versus predictive genetic testing

Answer 17

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

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 18

Retinoblastoma

Answer 18

Childhood ocular cancer
Follows the Knudson two hit hypothesis
- Retinoblastoma (Rb1) gene
-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 germ line

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 19

Familial Adenomatous Disease (FAP)

Answer 19

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
Colonoscopies, total colectomy late teens/early 20s

-Autosomal dominant inheritance

Question 20

Hereditary Non-Polyposis Colorectal Cancer (NHPCC)

Answer 20

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 21

HNPCC – Amsterdam Criteria

Answer 21

• One member diagnosed with colorectal cancer before age 50 years
• Two affected generations
• Three affected relatives, one of them a first-degree relative of the other two
• FAP should be excluded
• Tumours should be verified by pathologic examination

Question 22

BRCA1 & BRCA2 genes

Answer 22

• BRCA1&2 are involved in DNA repair
• ~10% of cases of breast cancer under 40 and ~25% of those with strong FH
• 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 23

Options for BRCA1 & BRCA2 gene carriers

Answer 23

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 24

Li Fraumeni Syndrome

Answer 24

-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
Poor prognosis

Question 25

More syndromes at the end of the lecture

Answer 25

slide 30