Genetics of Cancer

Question 1

Definition of somatic mutation

Answer 1

DNA change after conception

Occurs in any of the cells except germ cells and is not passed on

Question 2

Definition of germline (constitutional) mutation

Answer 2

Mutation in germ cells and can be passed onto offspring

Present in all cells

Question 3

What are the risk factors associated with cancer

Answer 3

Age
Environment
Exercise and obesity
Infections
Genetics, family history

Question 4

What are the possible consequences of somatic mutations

Answer 4

Damage in somatic cells, not passed onto children

Cell death
Damage in non coding/inactive DNA
Damage genes controlling cell growth

Question 5

What are the possible 3 negative effects of damage in genes involved in cell growth

Answer 5

Inactive tumour suppressor gene => faster cell division

Activate oncogenes (missense) => gain functions and faster cell division

New fusion genes (chromosomal rearrangements) => growth advantage

Question 6

Describe how a tumour can develop

Answer 6

Clonal expansion of genetically abnormal cells
Sporadic mutations that favour clonal expansion divide more rapidly => increased chance of more mutations

May result in a cancer that has several cells with different mutations

Question 7

What 3 genes are associated with cancer predisposition and their properties

Answer 7

Tumour suppressor genes
Oncogenes
DNA damage response/repair genes

Question 8

What are the properties of tumour supressor genes

• how can they become cancerous
• what can increase the risk of cancer here

Answer 8

Control cell growth rate, normally diploid

Sporadic cancer occurs with biallelic loss/mutation

Heterozygous constitutional mutation => increased risk

Question 9

What are the properties of oncogenes

-how can they become cancerous

Answer 9

Promote cell division

Cancer occurs when stuck in ‘on mode’

Question 10

What are the properties of DNA damage response/repair genes

-how can they become cancerous

Answer 10

Constantly repairs DNA

Cancer arises due to accumulation of mutations across genome

Question 11

What are the 3 DNA repair mechanisms

Answer 11

Mismatch repair
Double strand break repair
Nucleotide exision repair

Question 12

Describe mismatch repairs

• when would this be used
• how is DNA repaired

Answer 12

Replication errors (1 base errors)

• AG/CT mismatch
• Insertion/deletion
• Protein complex sees and binds to mispaired base
• DNA cut around error, mispaired nucleotide and neighbours removed, replaced with DNA polymerase
• Sealed with DNA ligase

Question 13

Describe double strand break repairs

• when would this be used
• how is DNA repaired

Answer 13

Xrays and ionising radiation
Antitumour agents

Non homologous end joining and homologous recombination used in repair

Question 14

Describe nucleotide exision repair

• when would this be used
• how is DNA repaired

Answer 14

UV light forming thymine dimers

Damaged bases cut out within a string of nucleotides and replaced with correct DNA

Question 15

Describe the inheritance of cancer susceptibility genes

Answer 15

Most are dominant with incomplete penetrance
May appear to skip generations
Individuals inherit altered cancer susceptibility genes, not cancer

Question 16

What are the 3 main features of familial cancers

Answer 16

Young age of onset of cancer
Multiple primary cancers in same person
Same cancer in many relatives/recognisable pattern in family

Question 17

What is the criteria used in a cancer risk assessment

Answer 17

Age
-young age at diagnosis

No

• several family members affected
• multiple or bilateral tumours in 1 person

Close relatives affected
-1st degree>2nd degree>3rd degree

Patterns

• rare tumour types
• tumour associations
• histopathology

Ethnicity
-founder mutations in some populations

Question 18

How can mutations affect the expression of cancer

Answer 18

Different mutations in different genes => different tumour risk profiles

Cancer is more likely to arise if replication rate is naturally high (epithelial cells in GI)

Double strand damage can’t be fixed due to damaged repair mech

Mutated tumour suppressor genes

Question 19

What are the 2 types of genetic mutation

Answer 19

Somatic

• DNA change after conception
• occurs in any of the cells except germ cells so not passed on

germline (constitutional)

• mutations in germ cells and can be passed onto offspring
• present in all cells

Question 20

What is the main cause of most cancers

Answer 20

Somatic mutations

Question 21

What are the 2 types of genetic tests

When would you use them

Answer 21

Diagnostic
-screen gene in affected person with cancer suspected to have a familial element

Predictive
-offered to close family if genetic susceptibility confirmed by initial diagnostic test

Question 22

Why would you treat constitutional cancers differently to somatic cancers

Answer 22

Higher chance of recurrence

Higher chance of primary cancer arising elsewhere

Question 23

How would you discover cancer predisposition genes

Answer 23

Predisposition genes rare but have high penetrance

Common but low penetrance genes by GWAS