Inherited Predisposition to Cancer

Question 1

What are inherited cancer predispositions?

Answer 1

An inherited increase in the risk of developing a disease

Question 2

Is inherited cancer predisposition common?

Answer 2

No it is rare with only approx 4% of cancers associated with genetic predisposition

Question 3

What are the characteristics of cancers with an inherited predisposition?

Answer 3

• Family history of (same) cancer
• Early age of onset (especially childhood)
• Multiple cancers in one individual
• High occurrence of rare cancer
• Premalignant conditions (eg polyps)

Question 4

What is a cancer predisposition gene?

Answer 4

• Genes in which rare mutations confer >2x relative risk of cancer
• At least 5% of individuals with relevant mutations develop cancer

Question 5

How many cancer predisposition genes are there?

Answer 5

114 across the genome affecting every chromosome apart from chromosome 20

Question 6

What type of genes are cancer predisposition genes?

Answer 6

• 103 are TSGs
• 11 are activated by mutations

Question 7

What are the inheritance patterns of the cancer predisposition genes?

Answer 7

• 65 autosomal dominant
• 28 autosomal recessive
• 16 both autosomal dominant and recessive
• 5 sex linked

Question 8

What is retinoblastoma?

Answer 8

• Eye cancer in children
• Affects 1 in 20,000 children
• 90% cases present in children <5
• Caused by mutation to TSG RB1
• Can be sporadic or familial

Question 9

What is the difference in hits between non-hereditary and hereditary cancers

Answer 9

Non-hereditary require 2 hits both by mutation whereas hereditary already contains a hit which has been passed down so it only requires 1 more hit

Question 10

What type of inheritance is predisposition?

Answer 10

It is inherited as dominant so a hit is in one allele but tumour development requires both alleles to be hit

Question 11

What is Li-Fraumeni syndrome?

Answer 11

• Rare inherited predisposition to a range of cancers
• Only diagnosed if the patient had sarcoma before 45 yrs old and has a relative with any cancer before 45 yrs old or a sarcoma at any age
• 50% risk of developing cancer by 40
• 90% risk of developing cancer by 60

Question 12

How can patients be clinically managed?

Answer 12

• genetic testing to identify carriers
• surveillance to detect cancers early
• MRI, blood tests, ultrasounds etc

Question 13

Give 2 examples of cancer predispositions cased by mutations to TSGs

Answer 13

Retinoblastoma and Li Fraumeni syndrome

Question 14

How common is breast cancer?

Answer 14

• 20% of all new cancer cases
• Affects 1 in 10 women, 1 in 100,000 men
• Average age of onset is approx 60

Question 15

Is breast cancer sporadic?

Answer 15

• Approx 75-80% of breast cancer is sporadic
• Somatic mutations are acquired over a lifetime
• There is no increased risk to family members beyond general population risk

Question 16

Is breast cancer familial?

Answer 16

• Only approx 10-15% of breast cancer is familial
• Characterised by an unclear inheritance pattern
• Generally not eligible for genetic testing

Question 17

What are the characteristics of hereditary breast cancer?

Answer 17

• 5-10% of BRCA mutations are associated with an inherited predisposition
• younger age of onset (before menopause)
• higher prevalence of bilateral breast cancer
• associated tumours in family members
• dominant inheritance pattern
• increased risk in BRCA1 compared to BRCA2 mutation

Question 18

What are the cellular functions of BRCA1/2?

Answer 18

• chromosome integrity
• repair ds breaks in DNA
• reactivate stalled DNA replication forks
• resolve R loops during transcription

Question 19

How many other breast cancer predisposition genes are there?

Answer 19

Approx 100 other genes that focus mainly on DNA repair and genome integrity