Inherited Cancer Genetics Flashcards
Where do cancer mutations 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
What is meant 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)
How can we identify patients with increased genetic predisposition?
Family history
Syndromic features
Tumour testing
Pathology of cancer
What are 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
What is tumour to germline testing?
Cancer patients now being offered large cancer gene panel sequencing of their tumour
If we find a disease causing change in a cancer predisposition gene on testing the tumour, it is possible it might also be in the germline
We can then offer a blood test to check this
What is the stratified prevention strategy?
The ‘stratified prevention’ strategy allows categorisation of the population into multiple groups with different interventions applied in the different groups
By stratifying the population into several groups according to genetic risk alone or combined with traditional disease risk factors such as age and family history standard public heath interventions could be applied differentially to each population stratum with potentially more efficient outcomes
What are the characteristics of cancer predisposition inhertance?
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 are the possible 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 information to help classify variant if possible
Disease causing (pathogenic) variant identified
- Manage as per gene specific protocol
- Can offer cascade screening to relatives
What are 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
What is Lynch syndrome?
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
What is the eligibility for Lynch syndrome- testing?
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 the patient
What is the carrier management of those with Lynch syndrome predisposition?
Carrier management Screening - Colorectal - Gastric - Symptom awareness Risk-reducing surgery - Hysterectomy +/- BSO Chemoprevention - Low dose aspirin Research Cancer management Family matters
