clinical cancer genetics Flashcards
where does the mutation occur
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
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)
high risk cancer predisposition genes are rare and dependent on cancer type
Breast cancer 5-10% Colon 5-10% Prostate 5-10% Ovarian 10-15% Melanoma 10% Pancreatic 10% Medullary thyroid 25% Retinoblastoma 40%
polygenic risk scores
Genetic testing of multiple low risk factors
Not currently performed on the NHS
Can indicate increased genetic susceptibility to cancer
Undertaken by looking for cancer associated SNPs found from Genome Wide Association Studies
summary of 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
genetic testing
ransition to WGS Increased mutation detection Increased understanding of mutagenesis Greater understanding of phenotypic spectrum/ cancer risk if ascertained outside “typical syndrome”
outcomes of diagnostic genetic testing
- no disease causing variant identified = manage on basis of family history and personal diagnosis
- variant of uncertain significance identified
- analyse variant with scientists
- manage on basis of personal and family history
- try to get info to help classify variant if possible - disease causing variant identified
- manage as per gene specific protocol
- can offer cascade screening to relatives
clinically actionable pathogenic variant identified in CPG
Manage according to gene specific protocol
Screening, Prevention and Early Detection (SPED) e.g.
Non-invasive imaging –often more frequent and starting at younger age
Invasive – often more frequent, starting at younger age
Chemoprevention
Risk reducing surgeries
predictive testing
A test in a WELL person to predict future risk
Protected against discrimination by moratorium with Association of British Insurers
If pathogenic variant not present can manage as population risk usually
If pathogenic variant present, manage as per gene specific protocol
describe 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
Screening
Risk-reducing surgery
Chemoprevention for BRCA2 carriers
Male BRCA2 carriers recommended to have annual PSA test
research
BRCA register
Lynch syndrome - background
Prevalence: 1 in 440
Accounts for ~1-3% of all CRCs
Mismatch repair
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
Lynch syndrome - 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
Lynch syndrome = carrier management
Screening Colorectal Gastric Symptom awareness Risk-reducing surgery Hysterectomy +/- BSO Chemoprevention Low dose aspirin Research Cancer management Family matters
