Familial Cancer Syndromes (5)

Question 1

Penetrance

Answer 1

Percentage with a gene change who develop the condition - modified by genetic variations/environmental factors

Question 2

Gatekeepers

Answer 2

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

Question 3

Caretakers

Answer 3

Improve genomic stability e.g. repair of mutations/carcinogen metabolism

Question 4

Landscapers

Answer 4

Control the surrounding stromal environment

Question 5

Tumour suppressor genes

Answer 5

Protect cells from becoming cancerous, loss of function increases the risk of cancer e.g. APC, BRAC1/2, TP53, Rb

Question 6

Oncogenes

Answer 6

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 7

Knudsen’s two hit hypothesis

Answer 7

• Sporadic - two hits required in single cell (recessive)

- Inherited - one additional hit required in a single cell (autosomal dominant)

Question 8

Most cancer syndromes are autosomal..

Answer 8

Dominant

Question 9

Cancer syndromes that are autosomal recessive

Answer 9

• MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia
• Appears to skip generations and may account for some sporadic cases

Question 10

Mutation types

Answer 10

• Splice site mutations
• Large deletions and duplications
• Translocations

Question 11

Sporadic cancer

Answer 11

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

Question 12

Familial cancer

Answer 12

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

Question 13

Most common type of cancers in children are

Answer 13

Brain tumours and haematological

Question 14

Retinoblastoma

Answer 14

• Childhood ocular cancer
• Rb1 gene (tumour suppressor)
• Genetic cases - one mutation is present in germline
• Inherited cases occur at younger average age
• Bilateral cases almost always germline

Question 15

How common is retinoblastoma?

Answer 15

Very rare - 1 in 15,000-30,000 live births

Question 16

Are there other cancer risks with retinoblastoma?

Answer 16

Yes e.g. osteosarcoma

Question 17

Familial Adenomatous Polyposis (FAP)

Answer 17

• Hundreds of bowel polyps/adenomas from teens onwards

- Colonoscopies, total colectomy late teens/early 20s

Question 18

How risky is FAP for bowel cancer?

Answer 18

up to 100% by 40 if not treated, accounts for 1% of all bowel cancers

Question 19

Features of FAP

Answer 19

CHRPE, desmoid tumours, osetomas

Question 20

What gene is involved in FAP?

Answer 20

APC tumour suppressor gene

Question 21

What inheritance is FAP?

Answer 21

Autosomal dominant inheritance

Question 22

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Answer 22

• Accounts for 2-3% of bowel cancers

- Polyps common, polyposis not

Question 23

What does polyposis mean?

Answer 23

Numerous internal polyps

Question 24

How risky is NHPCC for bowel cancer?

Answer 24

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

Question 25

Other cancer risks involved with NHPCC

Answer 25

Endometrial, ovarian, stomach, GU

Question 26

Genes involved in NHPCC

Answer 26

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

Question 27

What kind of inheritance is NHPCC?

Answer 27

Autosomal dominant

Question 28

Amsterdam Criteria for NHPCC shows what?

Answer 28

Who is at high risk

Question 29

Amsterdam Criteria for NHPCC

Answer 29

- 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 30

Benefits of colonoscopic screening in NHPCC

Answer 30

Remove polyps/early detection of cancer improving survival

Question 31

How often should you do colonoscopic screening in NHPCC

Answer 31

Every 18-24 months from 25

Question 32

NHPCC preventative surgery

Answer 32

Women may consider hysterectomy

Question 33

BRCA 1 and 2

Answer 33

10% of breast cancers under 40

Question 34

What kind of inheritance is BRCA 1 and 2?

Answer 34

Autosomal dominant

Question 35

BRCA 1 and 2 common in..

Answer 35

Jewish

Question 36

Increased risk of which cancers with BRCA 1 and 2

Answer 36

Breast cancer (80%), ovarian (BRCA1 40%, BRCA2 15%), prostate, melanoma, male breast cancer

Question 37

Options for BRCA 1 and BRCA 2 gene carriers

Answer 37

- Breast screening (annual MRI 30-50, annual mammography 35-40) - Risk-reducing mastectomies, BSO - Ovarian screening no use

Question 38

Li Fraumeni Syndrome

Answer 38

- P53 mutations, rare

Question 39

Li Fraumeni Syndrome inheritance..

Answer 39

Autosomal dominant

Question 40

Li Fraumeni Syndrome risk of cancer

Answer 40

50% by age 40, close to 100% in lifetime

Question 41

Li Fraumeni Syndrome, which cancers at risk of

Answer 41

Breast, sarcoma, brain, adrenocortical, leukaemia