Clinical cancer genetics Flashcards
What are the two types of mutations that occur in cancer ?
Constitutional (germline) mutations - in all body cells, present at birth, present in fertilised egg (from sperm/egg)
Somatic mutations - tumour-only mutations. genetic change occurs in cell, copying errors during cell division, DNA mutation within cell. mosaic. don’t give info about inherited risk, but about molecular pathways for targeted drug therapy.
What are germline mutations ?
Hereditary
Informs future cancer risk
Informs treatment decisions
Provides information for other family members
Inherited cancer is due to constitutional germline mutations
What are somatic mutations?
These are acquired
Informs treatment decisions
Provides reassurance for family and future children
-Sporadic cancer is due to tumour-only somatic mutations
-due to errors in DNA replication, repair, cell division processes
What are the three types of cancer patients ?
- Sporadic cancer
- Familial cancer - not 1 high-risk genetic factor but multiple low-risk genetic variants/factors. Most common inherited susceptibility to cancer. Multifactorial polygenic risk.
- High risk cancer susceptibility/predisposition gene - 1 genetic change which significantly increases cancer risk
What is the multifactorial/polygenic familial risk?
Larger proportion of familial cancers than high risk cancer predisposition genes
No single high risk gene identified
Disease Risk conferred through multiple lower risk genetic factors +/- environmental factors
No current testing available but is on the horizon
Use Family history as a proxy of polygenic familial risk. Family members share variants.
Increased screening is available for some cancer types in at risk individuals (e.g. breast, colorectal)
Identify multifactorial familial risk for screening, prevention + early detection + management pathways
High risk cancer predisposition genes are rare + dependent on cancer type?
Breast cancer 5-10%
Colon 5-10%
Prostate 5-10%
Ovarian 10-15%
Melanoma 10%
Pancreatic 10%
Medullary thyroid 25% - RET gene mutation drives the cancer
Retinoblastoma 40% - childhood cancer
Why do we try to identify patients with increased genetic disposition to cancer ?
- Provides reason for why developed cancer
- Informs medical management and surgical options - provide diff targeted therapies according to specific molecular mechanisms driving the cancer. e.g. opt for bilateral mastectomy bc high risk of second cancer. helps patient decide suitable treatment.
- Informs patients about future cancer risks - preventative methods after treat this cancer
- Informs relatives about cancer risk - access to screening/risk reducing surgery, preventing + early detection of cancer.
How can we identify patients with increased genetic predisposition to cancer ?
Family history
Syndromic features - e.g. in tumour that indicate it’s due to a high-risk gene? Pathology of Cancer histology/type?
Tumour testing - look for genetic changes within tumour - sporadic (tumour-only)/mutation in a known cancer predisposition gene = we can then check that it isn’t in patient’s germline
Pathology of cancer
Outline family history assessment
Three generational family history .
Bilateral cancer/ multiple cancer in same individual
Age of onset
Multiple cancer diagnosis of same type .
Closely related individual
Multiple cancer diagnosis or cancer related to specific CPG in closely related individuals (caused by same underlying genetic defect)
What are polygenetic risk scores?
Single value estimate of an individual’s genetic liability to a trait or disease.
Target to look for specific changes using SNP from GWAS that are known to be associated w certain cancer types
Is any SNP base subs more common in cancer cases than in controls? Then test for that using SNP chip for polygenic risk score.
What are syndromic features?
Very rare cancer predisposition genes
Flags on clinical examination
- Trichielomma - Cowden Syndrome - cancer predisposition syndrome caused by PTEN gene
- Mucocutaneous pigmentation - rare cancer predisposition syndrome Peutz-Jagher’s syndrome - STK11 gene mutations
Clinical signs indicating inheritied cancer susceptibility
What is stratified prevention ?
All women are offered screening from age of 47-50.
This is the categorization of the population into risk groups, each of whom would be offered a different intervention
Individuals with a family high risk can be offered further screening
Identify those w increased cancer risk to offer increased screening program - cost-effective.
Using family history as a proxy for increased familial risk
Stratified screening based on genetic risk, using family history as a proxy for genetic risk
What is Tamoxifen?
Tamoxifen = anti-oestrogen drug which has been shown to reduce the risk of women developing breast cancer from families with increased genetic susceptibility to breast cancer - Chemo prevention = use medication to reduce breast cancer risk
Give a summary of multifactorial /polygenic risk assessment
Larger proportion of familial cancers than high risk cancer predisposition genes
No routine genetic testing
Multiple lower risk genetic factors
Family history as a proxy of risk
Screening, prevention and early detection (SPED)
- Mammograms
- Colonoscopies
- Chemoprevention
When is genetic testing offered to patients for high risk cancer predisposition genes ?
Where there is a likelihood of finding a pathogenic variant >10%
What are the caveats of cancer predisposition genes ?
Even if a disease causing change is found , the risk of cancer is not 100%
Large range which may have other influences
The age of the patient , type of pathogenic variant and risk penetrance must be taken into account.
Describe cancer predisposition inheritance
Most inherited cancer predisposition genes are inherited in autosomal dominant fashion therefore 50% chance of passing it on to child
Heterozygous increases cancer risk
Outline autosomal recessive cancer predisposition inheritance
Sometimes ,autosomal recessive predisposition to cancer can occur with healthy carriers but when a child inherits 2 pathogenic variants.
MUTYH gene -colon polyps and cancer
Several autosomal dominant cancer predisposition genes are linked to rare autosomal recessive conditions (childhood onset cancer syndromes) when biallelic pathogenic variants are inherited e.g.BRCA2 is a Fanconi anemia gene
What are the different genetic tests which are offered ?
Single gene
NGS panel
(Next generation sequencing) - breast cancer, bowel cancer, multiple genes cause the cancer
WES
(Whole exome sequencing)
WGS
(Whole genome sequencing) - paired both tumour + germline
What are the outcomes of diagnostic genetic testing for high-risk cancer predisposition gene?
1.No disease causing variant is identified
-manage on basis of family history and personal diagnosis
=more likely to be polygenic multifactorial risk = still need ↑ screening even if not high-risk gene
- Disease causing (pathogenic) variant identified
- manage as per gene specific protocol
- Can offer cascade screening to relatives - Variant of uncertain significance identified
- Analyze variant with scientists
- Manage on basis of personal and family history
- Try to get information to help classify variant
- Majority of rare changes within a gene are not disease-causing
- Variants never seen before
What would happen if an actionable pathogenic variant is identified?
Screening, Prevention and Early detection
- Non invasive imaging -more frequent from a young age
- Invasive-more frequent
- Chemoprevention
- Risk reducing surgeries
What is predictive testing ?
This is a test in a well person to predict future risk
Protected against discrimination
If pathogenic variant not present can manage as population risk
If pathogenic variant us present, manage as per gene specific protocol
What are the genes which are most frequent monogenic causes for hereditary breast cancer ?
BRCA1 / BRCA2 genes = monogenic cause of hereditary breast cancers
-They account for 20% of familial breast cancer
Contribution to overall breast cancer
-Involved in DNA repair (homologous recombination repair) and regulation of transcription
-Disease causing variants result in an increased risk to develop certain cancers
-Founder mutations common in specific populations e.g Polish, Jewish
What is the carrier management ?
Offer women who carriers of BRCA mutations:
Screening - MRI scans of breast + Annual Mammograms
Risk-reducing surgery - uterine tubes, ovaries
Chemoprevention for BRCA2 carriers
More BRCA2 carriers recommended to have annual PSA test
What is Lynch syndrome ?
This is a familial colorectal, endometrial and ovarian cancer which is 1-3% of all cancers.
Caused by mismatch repair in (mutations )
MLH1,MSH2,MSH6 and pMS2.
High in young uterus cancers
How are patients checked for Lynch syndrome ?
A tumour test is offered to find four proteins produced by the genes .
Test on tumour to look for the 4 proteins produced by the 4 genes. Immunohistochemistry staining. Missing proteins suggest Lynch. Further tests - blood tests
The cancer risks are dependent on the gene and gender of the patient
What is some further lynch syndrome carrier management
Screening:
- colorectal
- gastric (H. pylori)
- symptom awareness
Risk reducing surgery - Hyseterectomy +/- BSO
Chemoprevention - Low does aspirin - 1/2 developing cancer risk when one has Lynch syndrome
Research
Cancer management
Family matters
- 5-10% high-risk cancer predisposition genes -
- Multifactorial
- 5-10% high-risk cancer predisposition genes - v. rare, high effect size
- Multifactorial - common variants, low effect size, but add up with other variants to increase overall cancer risk
Women w increased familial risk are given
yearly mammography screening program bc have increased risk of younger, more aggressive cancers = increased screening for women at increased risk 40-49yrs
Population women breast cancer risk
Moderate breast cancer risk
Moderate-high breast cancer risk
Population women breast cancer risk - 12-17%
Moderate breast cancer risk - 17-30% = category B1 surveillance
Moderate-high breast cancer risk - >30% = category B2 surveillance
see slide
Moderate-high breast cancer risk - >30%
has been a genetic test in family but no high risk gene but instead multiple polygenic risk factors in the family which are more significant than the moderate risk breast cancer risk (12-17%) families
-offer these annual mammograms ages 40-59yrs + 3-yearly mammogram after
Which gene mutations significantly increase breast cancer + ovarian cancer risk?
BRCA1
BRCA2 - also prostate cancer + pancreatic cancer
Having breast cancer = ……… risk of developing a second contralateral breast cancer
<50%
Why not chemoprevention for BRCA1 carriers?
BRCA1 carriers = Oestrogen-negative tumours
