Cancer Genetics

What role do genes play in cancer development?

Cancer develops when mutations affect genes that control cell growth, DNA repair and apoptosis.

What is a somatic mutation?

A mutation that occurs in body cells during life and is not inherited.

What is an inherited (germline) mutation?

A mutation present from birth that can be passed to offspring.

What percentage of cancers are hereditary?

About 5–10%.

What is a tumour suppressor gene (TSG)?

A gene that normally prevents uncontrolled cell growth.

What type of mutation usually affects tumour suppressor genes?

Loss-of-function mutations

What is a proto-oncogene?

A normal gene that stimulates the cell cycle.

What is an oncogene?

A mutated proto-oncogene that causes uncontrolled cell growth.

What type of mutation usually converts a proto-oncogene into an oncogene?

Gain-of-function mutation.

Tumour suppressor gene actions

• Some inhibit progression through the cell cycle

• Some promote apoptosis

• Some act as DNA repair genes.

What are DNA repair genes?

• A type of TSGs

• Act to minimise genetic alterations.

• Important in some commoner hereditary cancer predisposition syndromes e.g. Breast/ovarian and colorectal cancer

Sporadic cancer

• common

• late onset

• single primary tumour

familial cancer

• uncommon

• early onset

• often multiple primaries

how are most cancer predisposition syndromes inherited?

autosomal dominant fashion

what are most cancer predisposition syndromes due to?

inheritance of an altered TSG:

• involve subsequent inactivation of the wild-type (normal) gene copy

• Two hits – Knudson’s hypothesis 1971

how common is cancer?

common

– 1 in 2 lifetime risk for those born after 1960

what to look for when identifying cancer

family history:

• more than one individual in same family affected by similar cancers or cancers at related sites with early age of onset

individual:

• multiple primary tumours

• early age of onset

most high risk breast cancer families

• mostly BRCA1 & BRCA2

• less commonly TP53, PALB2, PTEN, CDH1

Male breast cancer suggests what family of cancer?

BRCA2

What type of genes are BRCA1 and BRCA2?

Tumour suppressor genes involved in DNA repair: Repair double-strand DNA breaks by homologous recombination.

BRCA1 mutation

• approx 72% risk of breast cancer (by 80 yrs) (population risk approx. 10%)

• Approx 44% risk of ovarian (or fallopian tube) cancer by age 80 (population risk approx. 1.5%)

BRCA2 Mutation

risks to age 80:

• 69% for breast cancer

• 17% for ovarian or fallopian tube

Risks in male carriers:

• 4% for breast cancer in men (rare in population)

• 27-41% for prostate cancer (18% in population)

modifier genes

• Many (modifier) genes that confer an increased susceptibility to breast cancer

• Variants in these are common (in > 5% of population).

• Each modifier genetic variant generally confers a small effect e.g. a 10-20% increased risk for each

DNA testing for BRCA1/2 mutations

• for affected individual who has at least a 10% chance of possessing a mutation

• Increased use of “Next Generation Sequencing”

• Important to store DNA from blood of affected individuals who have family history of cancer (to permit future mutation analysis)

Breast cancer screening/prevention

Females: breast examinations annually and screening by MRI & mammography

BRCA1 or BRCA2 mutation carriers may also be offered:

• prophylactic bilateral mastectomies

• prophylactic oophorectomies

• Males: annual PSA from 40 for BRCA2

What type of genes are MLH1 and MSH2?

DNA mismatch repair genes

What is the APC gene associated with?

Familial adenomatous polyposis (FAP)

what gene is mutated in Li-Fraumeni syndrome?

TP53

What feature in a family history suggests inherited cancer?

More than one family member with similar or related cancers.

What age feature suggests inherited cancer?

Early age of onset

what feature in an individual suggests inherited cancer?

Multiple primary tumours

how do sporadic cancers differ from familial cancers?

Sporadic cancers are common and late onset; familial cancers are uncommon and early onset

What gene mutations can cause ovarian cancer?

• BRCA1

• BRCA2

• HNPCC gene: MLH1 or MSH2

Why is ovarian cancer screening currently unavailable?

lack of evidence for benefit

Ovarian cancer prophylactic surgery

bilateral salpingo-oophorectomy after childbearing complete

New treatment for ovarian cancer

Poly ADP ribose polymerase (PARP) inhibition - olaparib:

selective for tumor cells which depend on that enzyme for DNA repair

Colon cancer has a strong genetic basis in how many cases?

5-10%

What is the most common inherited colorectal cancer syndrome?

Lynch syndrome (HNPCC)

Which genes are most commonly mutated in Lynch syndrome?

MLH1 and MSH2

• 2-3% of cancers

What gene is mutated in familial adenomatous polyposis (FAP)?

APC

• 0.5% of cancers

What inheritance pattern is typical of most inherited colon cancer syndromes?

Autosomal dominant

What is lynch syndrome?

• HNPCC (Hereditary non-polyposis colon cancer)

• Less than 10 polyps

• Due to the inheritance of mutation in MMR system genes (important for accurate DNA replication)

Cancer risk from lynch syndrome

• Colon: 50-60% cf, 6-7% population

• endometrial: 50% cf, 3% population

• ovarian: 10-20% cf, 2% population

• stomach: 10-20%cf, 4% population

Screening used for those at risk of lynch syndrome

colonoscopes

screening for those at high risk of colon cancer

• 2 -yearly colonoscopies from age of 25 -75

• H. pylori screening for stomach

what can reduce the risk of colorectal cancer?

• Aspirin

• Offer hysterectomy (with bilateral salpingo-oophorectomy) after childbearing complete

Which genes cause lynch syndrome/ HNPCC

• MLH1 approx 50%

• MSH2 approx 40%

• MSH6 7-10%

• PMS2 <5%

Familial Adenomatous Polyposis (FAP)

Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) in 80%

FAP screening

Annual bowel screening from age 11

MYH/MUTYH polyposis

• Aut. recessive (not aut. dominant) inheritance

• like a mild form of FAP

• Normal function: base excision repair (BER) gene

• high risk of carcinoma

• 2 yearly colonoscopy

What is Li Fraumeni syndrome?

Rare Aut Dom cancer predisposition syndrome for:

– Breast cancer

– Brain tumours

– Sarcoma

– Leukaemia

– Adrenocortical carcinoma

Cancer risk increases from Li Fraumeni syndrome

50% by age 30, 90% by 50

What causes Li Fraumeni syndrome?

Mutations in master control gene, TP53

What is the lifetime breast cancer risk in BRCA1 mutation carriers?

~72%