Cancer genomics 1: Inherited cancer genetics Flashcards
Where can DNA mutations occur that can lead to cancer developing and why is this information useful?
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
Describe multifactorial/polygenic familial risk for inherited cancer susceptibility
- 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, these multiple low risk factors accumulate to increase the overall risk of developing cancer
- No current testing available
- Family history as a proxy of risk
- Increased screening is available for some cancer types in at risk individuals (e.g. breast, bowel)
Why is it important to identify patients with increased genetic predisposition to cancer?
- Informs medical management and surgical options
- Provides reason for why cancer developed
- Informs patient about future cancer risk
- Informs relatives about cancer risk - access to screening/risk reducing surgery (e.g. masectomy, hysterectomy)
What factors are used to assess genetic predispostion to cancer?
- Family history
- Polygenic risk scores
- Personal history
- Cancer history
- Pathological and molecular features of cancer
How is a family history used to assess inherited cancer susceptibility?
Family history can show:
- Bilateral cancer or multiple cancers in the same individual
- (Young) Age of onset
- Multiple cancer diagnoses of same type in closely related individuals
- Multiple cancer diagnoses of cancer related to specific CPG in closely related individuals
What are polygenic risk scores?
- Genetic testing of multiple low risk factors
- Not currently performed on the NHS
- Can indicate genetic susceptibility to cancer
- Undertaken by looking for cancer associated SNPs (single nucleotide polymorphisms) from GWAS
What gene is associated with atypical teratoid rhaboid tumour?
SMARCB1
What cancers are associated with TP53 gene?
- Choroid plexus tumour
- Anaplastic rhabdomyosarcoma
- Adrenocortical cancer
What cancers are associated with BRCA1/2 genes?
- Triple negative breast cancer (BRCA1)
- High grade serous ovarian cancer (BRCA1/BRCA2)
What cancer is associated with RET gene?
Medullary thyroid cancer
What cancer is associated with SDHx genes?
Paraganglioma/phaeochromocytoma
What cancer is associated with DICER1 gene?
Sertoli-Leydig ovarian tumour
What cancer is associated with FH gene?
Type 2 papillary renal cancer
What syndromic features can be associated with inherited predisposition to cancer?
- Trichilemmoma
- Mucocutaenous pigmentation
Describe constitutional vs somatic mutation?
- Constitutional - Mutations present in all of the body’s cells, including germ cells, and can therefore be passed on to offspring
- Somatic - Arise in an individual’s tissues throughout their lifetime in tissues other than the germ cells, so cannot be passed on to offspring
Describe germline testing of tumours
- Cancer patients now being offered large cancer gene panel sequencing of their tumour
- If a disease causing change in a cancer predisposition gene on the tumour is found, it could be possible it might be in the germline
- Blood tests can be offerred to check this
What are the possible outcomes of genetic testing?
- No disease causing variant identified - Manage on basis of family history and personal diagnosis because there’s still the multifactorial/polygenic possible familial risk
- Variant of uncerstain 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 the benefits of genetic testing?
- Increased mutation detection
- Increased understnading of mutagenesis
- Greater understanding of phenotypic spectum/cacer risk if ascertained outside ‘typical syndrome’
Describe hereditary breast cancer and ovarian cancer syndrome and its management
- BRCA1 and BRCA 2 genes
- PALB2, ATM, CHEK2, RAD51C, RAD51D
- Most frequent mongenic causes for hereditary breast cancers
- Account for almost 20% familial breast cancer
- Contribution to overall breast cancer approx 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
Depending on risk, screening, surgeries, or chemo prevention etc may be used to manage
Describe lynch syndrome and its management
- Prevalence: 1 in 400
- Accounts for 1-3% of all colorectal cancers
- Mismatch repair
- MLH1, MSH2, MSH6 and PMS2
- Disease-causing 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, sebaceous skin tumours
- 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
- Management can include:
- Screening - Colorectal, symptom awareness
- Risk-reducing surgery - Hysterectomy +/- BSO
- Chemoprevention - Daily aspirin
- Research
- Cancer managment
- Reproductive options
Describe stratified prevention
Categorisation of population into risk groups, each of whom would be offered a different intervention
By stratifying the population into several groups according to genetic risk alone or combined with traditional disease risk factors (age, family history), standard public health interventions could be applied differentially to each population stratus with potential for more effective outcomes
Describe the 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
What is the threshold for high risk CPGs?
Where likelihood of finding a pathogenic variant is >10%
How are most inherited cancer predispositions inherited? What can happen occasionally?
In autosomal dominant fashion, therefore 50% chance of passing on to child (male or female)
What is the management plan if a clinically actionable pathogenic variant is identified in CPG?
- Manage according to gene specific protocol
- SPED
- Non-invasive imaging - Often more frequent and starting at younger age
- Invasive - Often more frequent, starting at younger age
- Chemoprevention
- Risk reducing surgeries
Describe the use of predictive testing
- A test in a healthy 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
How can we identify patients with increased genetic predisposition to cancer?
- Family history
- Pathology of cancer
- Syndromic features
- Tumour testing
