Clinical Cancer Genetics Flashcards
How is genetic info encoded?
Genetic info is encoded by DNA
Stretches of DNA codes for genes which are packaged into chromosomes present in every cell nucleus in the human body.
What is the importance of genetic in cancer?
Significant for detecting people with an increased lifetime risk of developing cancer due to genetic factors
How is cancer risk reduced in those with cancer genetic risk?
To reduce their risk of cancer due to genetic risk we submit them into the following programmes:
- Screening
- Prevention
- Early detection
What is DNA?
Deoxyribonucleic acid (DNA) is a molecule encoding the genetic instructions used in the development and functioning of living organisms
What 4 bases form DNA?
Made up of 4 nucleotides or “bases” A = Adenine T = Thymine C = Cytosine G = Guanine
Runs in 5’ –> 3’ direction
opposing strand is 3’ –> 5’
What are genes?
Consist of sections of DNA which the cell translates into proteins
Genes tell the body how to grow, develop and function
How many genes are there in humans?
~ 20,000 genes in the human genome
2 copies of most genes – one on each chromosome
What is the human genome?
The entire length of DNA contained in human cells; 3 billion bases
How many genetic variants are there from person to person?
We have ~5million different genetic changes compared to another unrelated person
What is the use of genetic variation?
- Makes us unique “polymorphisms”
- Basis for evolution
- Basis for disease
- Caused by intrinsic errors in DNA replication and repair
- Caused by external factors
How odes genetic variation affect disease?
Genetic variation may influence our chance of developing disease
Describe the changes in normal cell division that occur leading to cancer
Normal cells divide, replicating their DNA before division
DNA replication is complicated and results in errors in a gene/s (i.e. a somatic mutation)
Normal cells die when an error cannot be repaired
How does cancer arise from incorrect cell replication?
Cancer results when mutations accumulate, cell does not die and cell growth is uncontrolled
How common is cancer?
Cancer is a common disease in humans
There is a 1 in 2 lifetime risk of developing cancer
What causes cancers?
Most cancers caused by combinations of genetic, environmental and lifestyle factors – multifactorial/sporadic - due to acquired (somatic) mutations within a cell giving it a growth advantage
What % of cancers are due to inheritance?
Only ~5-10% of cancers are due to the inheritance of a single cancer susceptibility gene
How do somatic mutations arise?
External factors like smoking, exposure to UV causes a permanent change to the DNA, known as a mutation
What is a somatic mutation?
Somatic mutations are just in that one cell but not in every cell in the body
Mutation in tumour only (e.g. breast)
- Occur in non germline tissues
- Non Heritable
How many of the genetic variations normally occurring from person to person are de novo?
5 million differences per person
10,000 of those variants will be in protein coding genes of those, about 40-100 will be de novo
What are germline mutations?
- Present in egg or sperm
- Inheritable
- Cause cancer family syndrome
Outline features of sporadic cancers
- No increased risk of other cancers
- Usually small increased risk to relatives
- No genetic testing indicated
- Normal clinical management for affected individuals
Describe the features of hereditary cancers
- High risks of recurrence/other associated cancers
- High cancer risks in relatives
- We can offer testing to at risk individuals
- We can offer screening and preventative management to gene carriers
- May alter treatment of affected individuals
Why are most cancers sporadic?
Most cancers are sporadic due to acquired mutations which only occur in cancer cells
What causes hereditary cancers?
A smaller proportion of cancers are due to inherited genetic changes
- Multiple lower risk genetic variants; multifactorial / polygenic risk
- Single high risk genetic variant in a cancer predisposition gene
How common are high risk CPGs?
High risk cancer predisposition genes are very rare within the population but if present is very likely to cause cancer e.g. Tp53 mutation = 9/10 cancer risk
How likely are common variants to cause cancer?
Common variants in the populations are less likely to cause cancer alone, but higher numbers of common variants increase the risk of cancer development
How common are multifactorial risks?
Multifactorial cancer risks are very common
There is an increased multifactorial risk where there are clusters of the same types of cancer
What causes multifactorial risks to occur?
These are due to SNPs (single base mutations) that are more common in cases than controls - can test for these
What is reduced penetrance?
The idea that NOT every person with a germline mutation develops the disease
Give examples of the high risk cancer predisposition genes (CPGs)
High risk cancer predisposition genes:
- Breast cancer 5-10%
- Ovarian 10%
- Colon 5-10%
- Melanoma 10%
- Medullary thyroid25%
- Retinoblastoma 40%
- Prostate 5-10%
- Pancreatic 10%
Which genes are targeted in cancer?
Different classes of genes are targeted in cancer, which function in normal cell regulation
Give examples of cancer susceptibility genes targeted in cancer
Growth promoting proto-oncogenes
- RET in MEN2
Growth inhibiting tumour suppressor genes
- RB1 in retinoblastoma
Genes involved in DNA damage repair
- BRCA1 and BRCA2 genes in breast/ovarian cancer
What other mechanisms of oncogenesis are there?
- Epigenetic mechanisms of oncogenesis
- Chromosomal aberrations
What points should be covered when taking a family history?
- 3 generation family history
- Ask about consanguinity
- Ethnic background
- Types and ages of all cancers 🡪 specifically ask this
Why is a family history not enough to diagnose?
Some individuals with a hereditary predisposition to cancer do not have a family history of cancer
What should we be wary of when taking family history?
Look for multiple cancer diagnoses of cancers related to specific CPG in closely related individuals e.g. BRCA gene mutations increase risk of breast and ovarian cancer
Breast cancer affects 1 in 8 women across UK, very rare if <40
Unusual to have sporadic cancer at young age - red flag
What is the effect of lynch syndrome?
Lynch syndrome caused by different set of mutations in cancer predisposition genes tends to cause bowel, ovarian, womb and gut cancers
Why is it important to test the pathology of the cancer?
Certain pathological subtypes of cancer increase risk of high risk CPGs
Name examples of high risk CPGs
- High grade serous ovarian cancer: BRCA1/2
- Medullary thyroid cancer: RET
- Triple negative breast cancer: BRCA1/2
- Type 2 papillary kidney cancer: FH
Why is it significant to carry out molecular testing of cancer?
Tumour testing may identify genetic changes which indicate inherited risk
How is molecular testing doublechecked?
Check with blood test e.g.
- Immunohistochemistry of mismatch repair genes in Lynch syndrome
- BRCA gene sequencing in ovarian cancer
What causes syndromic effects in cancer?
There are High risk syndromic cancer genes as well which present with identifiable syndromic features
What is trichilemomma?
Tricholemmoma is a benign tumour originating from the outer root sheath of the hair follicle
What are the syndromic features of trichilemmomas?
present as well-defined, smooth, asymptomatic papules or verrucoid growths on the head / face
What causes trichilemmomas?
Trichilemmoma strongly associated with P10 gene mutations causing cowden syndrome - increased risk of thyroid, breast and womb cancer: v rare
What is the consequence of STK11 gene mutations?
STK11 gene mutations causes peutz-jeghers syndrome associated with an increased risk of breast cancer and bowel polyps
Summarise how to assess a cancer risk
- Take a 3 generational family history
- Ages, types of cancer, no. of affected relatives
- Ethnic origin; higher rate of CPG in some popn. - Consider cancer types in detail
- ?increase chance of high risk (CPG) - Look for rare syndromic features
- can indicate high risk CPG - Use National Genomic Test Directory Eligibility Criteria
to decide if genetic testing is indicated
Describe how you would manage a patient with a multifactorial riisk with <10% CPG chance ?
Multifactorial / polygenic risk: <10% chance of CPG or gene testing is negative
We would offer screening, prevention and early detection advice (SPED)
What is chemoprevention?
Taking medicine to reduce cancer risk
What drugs are available for breast cancer?
Breast cancer: Tamoxifen / selective estrogen reuptake modulator (SERM)
What are the side effects of chemoprevention of breast cancer?
Reduce cancer risk but produce side effects - menopausal symptoms
What drug is used to reduce risk of colorectal cancer?
Colorectal cancer: daily aspirin in multifactorial cancer reduces risk
What considerations for the individual should be assessed before genetic testing?
Recurrence risks
Risks of other cancers
What are the implications for relatives when genetic testing for CPGs?
- How to share information
- Concerns about children
- Predictive testing
Family planning options (e.g. prenatal, PGD)
What is diagnostic testing?
Diagnostic - to confirm whether a CPG has causes the cancer
What is predictive testing?
Predictive testing - to identify if an unaffected person carries a CPG - insurance implications
What are the possible genetic testing outcomes?
> no genetic variant identified
disease causing variant in CPG identified
variant of uncertain significance (VUS) identified
What are the next steps for no genetic variant identified?
Screening and management on personal and family history
Referral for screening/further management only if indicated on above assessment
Reassuring for patient but reiterate participation in population screening programmes
How do we follow an identified CPG causing disease?
Screening and management tailored to specific CPG
Should be reviewed by NHS clinical genetics service
What do we do if a VUS is identified?
Benign until proven guilty
Referral for screening/further management only if indicated on above assessment
May be anxiety provoking for patients
Need to understand how common genetic variant is and that most VUS are benign
