Inherited predisposition to cancer

Question 1

What percentage of cancers are inherited?

Answer 1

• 4% associated with genetic predisposition

- most common = colon and breast cancer

Question 2

What are the characteristics of cancers with an inherited predisposition?

Answer 2

• family history of same cancer
• early age of onset, esp. childhood
• multiple cancers in one individual
• high occurrence of rare cancer
• premalignant conditions eg. polyps

Question 3

What are cancer predisposition genes?

Answer 3

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

Question 4

What are the inheritance patterns and mechanisms of cancer predisposition genes?

Answer 4

• 103 are TSG
• 11 are activated by mutation
  inheritance pattern :
• 65 autosomal dominant
• 28 autosomal recessive
• 16 are both autosomal dominant and recessive
• 5 sex linked

Question 5

Describe the two-hit hypothesis in non-hereditary versus hereditary cancers

Answer 5

Hereditary - inherit one mutated allele, doesn’t take long till they acquire another mutation = makes process faster in comparison to non-hereditary

Question 6

Describe Li-Fraumeni syndrome

Answer 6

• rare inherited predisposition to a range of cancer
• diagnosed when the patient has all of the following :
• sarcoma at < 45 years
• 1st degree relative with any cancer < 45 years
• another 1st (or 2nd) degree relative with any cancer < 45 yo or sarcoma at any age

Question 7

Clinical management of patients

Answer 7

• genetic testing to identify carriers
• surveillance to detect cancers early - resection, rather than chemo or radiotherapy
• MRI, blood tests, colonoscopy, dermatological exams, physical exams, ultrasound
• screening exerts a high emotional and psychological toll but is accepted by patients

Question 8

Breast cancer stats

Answer 8

• 20% of all new cancer cases
• affects 1 in 10 women, 1 in 100,000 men
• avg. age of onset = 60

Question 9

What are the 3 forms of onset of breast cancer?

Answer 9

• sporadic = acquire mutations over lifetime
• familial = poorly described reasons for clustering within families
• hereditary

Question 10

Describe sporadic breast cancer

Answer 10

• 75-80% of breast cancer is sporadic and not inherited
• onset is later in life
• somatic mutations are acquired over a lifetime
• no inc risk to family members

Question 11

Describe familial clustering of cancer

Answer 11

• 10-15% of breast cancer
• chance, common environmental influences, undiscovered gene mutation
• characterised by - unclear inheritance pattern, unilateral disease, later onset
• generally not eligible for genetic testing

Question 12

Describe hereditary breast cancer

Answer 12

• 5-10% of BrCa are associated with an inherited predisposition
• younger age of onset
• higher prevalence of bilateral breast cancer
• associated tumours in family members
• dominant inheritance pattern
• multiple affected individuals across multiple generations

Question 13

What are the 2 genes associated with breast cancer/

Answer 13

• BRCA1 + BRCA2
• dominant inheritance
• incomplete penetrance
• risk is higher for BRCA1
• BRCA2 = increased risk of other cancers

Question 14

What are the cellular functions of BRCA1/2

Answer 14

• chromosome integrity
• repair double strand breaks in DNA
• reactive stalled DNA replication forks
• resolving R loops during transcription

Question 15

What are the other breast cancer predisposition genes?

Answer 15

• 100 genes
• DNA repair and genome integrity
• PTEN, ATM, PALB2

Question 16

Clinical implications of identifying mutations

Answer 16

1. prevention : prophylactic surgery, chemoprevention, screening
2. aid diagnosis and management : extent of surgery, platinum therapy
3. provide information : why the cancer occurred, evaluate risk for family members