Clinical cancer genetics

Question 1

What are constitutional (germline) mutations?

Answer 1

→ Hereditary
→ Informs future cancer risk
→ Informs treatment decisions
→ Provides information for other family members

Question 2

What are somatic mutations?

Answer 2

→ Acquired
→ Informs treatment decisions
→ Provides reassurance for family and future children

Question 3

What do we mean by Multifactorial/polygenic familial risk?

Answer 3

→ No single high risk gene identified
→ Risk conferred through multiple lower risk genetic factors +/- environmental factors
→ No current testing available but is on the horizon
→ Family history as a proxy of risk
→ Larger proportion of familial cancers than high risk cancer predisposition genes
→ Increased screening is available for some cancer types in at risk individuals (e.g. breast, colorectal)

These people who carry this higher risk therefore have a higher chance of getting cancer.

Question 4

What sorts of things/tests can we do to identify patients with increased genetic predisposition to cancer?

Answer 4

→ Family history
→ Syndromic features
→ Tumour testing
→ Pathology of cancer

Question 5

Summary of lecture 1

Answer 5

Inherited susceptibility to cancer can be due to:

→ Multifactorial/polygenic risk
→ High risk cancer predisposition gene
→ Factors to assess genetic predisposition include:

a. Family history
b. Polygenic risk scores
c. Personal history
d. Cancer history
e. Pathological and molecular features of cancer

Question 6

What is involved in a multifactorial/polygenic risk assessment?

Answer 6

→ Larger proportion of familial cancers than high risk cancer predisposition genes (CPGs)
→ No routine genetic testing
→ Multiple lower risk genetic factors
→ Family history as a proxy of risk
→ Screening, Prevention and Early Detection (SPED) e.g.
Mammograms
Colonoscopies
Chemoprevention

Question 7

How are most cancer predispositions inherited and what are other less common ways this can happen?

Answer 7

→ Most inherited cancer predispositions inherited in autosomal dominant fashion therefore 50% chance of passing on to child (male or female)

→ Occasionally, autosomal recessive predisposition to cancer can occur, with healthy carriers but when a child inherits 2 pathogenic variants (e.g. MUTYH gene, there is a predisposition to colon polyps and cancer)

→ Several autosomal dominant cancer predispositions are linked to autosomal recessive conditions in rare cases when biallelic pathogenic variants are inherited, e.g. BRCA2 is a Fanconi anaemia gene, ATM = ataxia telangiectasia

Question 8

What do we know about Hereditary Breast and Ovarian Cancer syndrome? (BRCA1 and BRCA2 genes)

Answer 8

→ Most frequent monogenic causes for hereditary breast cancers
→ Account for ~20% of familial breast cancer
→ Contribution to overall breast cancer ~2%
→ Involved in DNA repair and regulation of transcription

→ Disease-causing (pathogenic or likely pathogenic) variants result in an increased risk to develop certain cancers
→ Founder mutations common in specific populations e.g. Polish, Ashkenazi Jewish

Carrier management involves:
Screening
Risk-reducing surgery
Chemoprevention for BRCA2 carriers
Male BRCA2 carriers recommended to have annual PSA test
Research
BRCA register

Question 9

What do we know about Lynch syndrome?

Answer 9

→ Prevalence: 1 in 440
→ Accounts for ~1-3% of all CRCs
→ Mismatch repair
due to mutations in either: MLH1, MSH2, MSH6 and PMS2
→ Disease-causing (pathogenic or likely pathogenic) variants result in an increased risk to develop certain cancers
→ Particularly colorectal, endometrial and ovarian
→ Other LS-associated cancers: small bowel, gastric, brain, ureter, renal pelvis, hepatobiliary, pancreatic and sebaceous skin tumours

Testing Eligibility:
→ Loss of protein expression via IHC in tumour sample
→ Amsterdam criteria: ~50% pick-up rate
3:2:1 rule: 3 affected family members, 2 generations, 1 under 50
→ Test directory criteria

Cancer risks – dependent on the gene and gender of patient

Carrier management:
Screening
Colorectal
Gastric
Symptom awareness
Risk-reducing surgery
Hysterectomy +/- BSO
Chemoprevention
Low dose aspirin
Research
Cancer management
Family matters

Question 10

List some factors that indicate an increased genetic risk of cancer

Answer 10

Factors indicating an increased genetic risk of cancer are:

→ cancer at a younger age
→ multiple cancers in the same person (the same cancer e.g. bilateral breast cancer) or related cancers (e.g. breast and ovarian cancer)
→ relatives with the same or related cancers
→ certain histological subtypes of cancer (e.g. medullary thyroid cancer)