Clinical cancer genetics Flashcards
What are some differences between Constitutional (germline) mutations and somatic mutations?
CONSTITUTIONAL (GERMLINE) MUTATIONS: Hereditary Informs future cancer risk Informs treatment decisions Provides information for other family members
SOMATIC MUTATIONS:
Acquired
Informs treatment decisions
Provides reassurance for family and future children
What are some differences between Constitutional (germline) mutations and somatic mutations?
CONSTITUTIONAL (GERMLINE) MUTATIONS: Hereditary Informs future cancer risk Informs treatment decisions Provides information for other family members
SOMATIC MUTATIONS:
Acquired
Informs treatment decisions
Provides reassurance for family and future children
What do we mean by Multifactorial/polygenic familial risk?
Larger proportion of familial cancers than high risk cancer predisposition genes
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
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.
What sorts of things/tests can we do to identify patients with increased genetic predisposition to cancer?
Family history
Syndromic features
Tumour testing
Pathology of cancer
Summarise lecture so far
Inherited susceptibility to cancer can be due to
Multifactorial/polygenic risk
High risk cancer predisposition gene
Factors to assess genetic predisposition include
Family history
Polygenic risk scores
Personal history
Cancer history
Pathological and molecular features of cancer
What is involved in a multifactorial/polygenic risk assessment?
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
How are most cancer predispositions inherited and what are other less common ways this can happen?
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
What do we know about Hereditary Breast and Ovarian Cancer syndrome? (BRCA1 and BRCA2 genes)
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
What do we know about Lynch syndrome?
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
List some factors that indicate an increased genetic risk of cancer
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)
