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Clinical pathology specialities: Clinical Genetics > Clinical Genetics: Clinical Cancer Genetics > Flashcards

Clinical Genetics: Clinical Cancer Genetics Flashcards

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1
Q

What can we do to reduce cancer risk in people at increased genetic risk?

A
  • Screening
  • Prevention programmes
  • Early Detection programmes
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2
Q

What is DNA?

A
  • A molecule which contains the human genetic code
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3
Q

What is a gene?

A
  • A functional unit that consists of sections of DNA which the cell translates into proteins
  • Contains the instructions to tell the body how to grow, develop and function
  • Aroeund 20,000 genes in the human genome
  • Genome contains 2 copies of most genes – one on each chromosome
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4
Q

What is the human genome?

A
  • The entire length of DNA contained in human cells
  • 3 billion bases
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5
Q

How much genetic variation is there between 2 unrelated people?

A
  • Around 5 million different genetic changes compared to another unrelated person
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6
Q

What is the risk that someone will develop cancer within their lifetime?

A
  • There is a 1 in 2 lifetime risk of developing cancer
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7
Q

What are the main reasons for the development of cancer within an individual?

A
  • Most cancers are “sporadic” – due to acquired (somatic) mutations within a cell giving it a growth advantage
  • Some genetic changes we are born with may also influence our lifetime cancer risk (inherited cancer risk)
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8
Q

What % of cancers are sporadic and what % of cancers are classed as other types?

A
  • Sporadic - 65%
  • Familial cancer (inheritance of multiple lower risk genetic variants; known as multifactorial/polygenic risk) - 25%
  • High risk genes (single high risk genetic variant of cancer predisposition gene) - 10%
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9
Q

What are some of the things that cause sporadic cancers?

A
  • Raective oxygen species
  • UV light/ionising radition
  • Ineffective DNA repair mechanisms
  • Carcinogens
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10
Q

What are the different types of changes that contribute to a person’s inherited cancer risk?

A
  • High risk changes
    • Cancer predisposition genes
  • Moderate risk changes
  • Low risk changes
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11
Q

What does the following graph show about inherited cancer risk?

A
  • X axis = How common a genetic variant is within the population (allele frequency)
  • Y axis = How likely genetic variant is to cause cancer (effect size)
  • Shows that genetic variants in cancer predisposition genes are very rare but have a very likely chance of causing cancer if they’re inherited
  • Also shows that common genetic variants will be inherited by quite a lot of people within the population but don’t have a high risk of causing cancer
    • Only having 1 common genetic variant means you probably won’t develop cancer
    • However, having 30 common genetic variants will increase your risk of developing cancer to quite a high level
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12
Q

How does a polygenic risk score allow you to calculate the risk of someone developing cancer?

A
  • Allows you to look at the number common SNPs associated with cancer that a person has which is then used to define that person’s lifetime risk of developing a particular cancer
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13
Q

How can you test for the number of common genetic variants (SNPs) associated with cancer a person has?

A
  • Genome wide association studies (GWAS)
  • Polygenic risk scores
  • NOTE: SNPs more common in people with cancer (cases) compared to people without (controls)
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14
Q

What hapens to the risk of developing a particular cancer if somone is found to have multiple common genetic variants associated with cancer?

A
  • If you have multiple common genetic varinats associated with cancer then your risk of developing cancer is pushed up compared to normal distribution (more likely to develop cancer)
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15
Q

For each of the following cancers state how likely that cancer is to be caused by a high risk gene and name the most likely high risk gene that causes that cancer

Breast cancer

Ovarian

Colon

Melanoma

Medullary thyroid

Retinobalstoma

Prostate

Pancreatic

A
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16
Q

When conducting a family history assessment to see if there’s an increased inherited risk what do you look for?

A
  • You look at 3 generations within the family and see if:
  • The same individual has/had bilateral cancers or multipe cancers
    • ​Indicates increased inherited genetic risk
  • Young age of onset for a particular cancer - e.g. breast cancer in individual under age of 40
    • Indicates increased inherited genetic risk as it’s unusual to have young age of onset in sporadic cancer
  • Multiple cancer diagnoses of same type in closely related individuals
  • Multiple cancer diagnoses of cancers related to same cancer predispostion gene in closely related individuals
    • E.g. Presence of genetic variant in BRCA gene would increase risk of both breast and ovarian cancer
17
Q

What types of tests are conducted when testing for cancer?

A
  • Look at pathology/histiological subtype of cancer - certain pathological subtypes of cancers have higer risk of being caused by high risk CPGs e.g.
    • High grade serous ovarian cancer: BRCA1/2
    • Medullary thyroid cancer: RET
  • Molecular testing - Tumour testing may identify genetic changes which could indicate inherited risk (need to check with a blood test) e.g.
    • Immunohistochemistry of mismatch repair genes in Lynch Syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC)
    • BRCA gene sequencing in ovarian cancer
18
Q

What are some syndromic features that may be signs of particular inherited risk cancers?

A
  • Trichilemmoma (small white bumps) - strongly associated with mutations of p10 gene which causes cowden syndrome which increases risk of thyroid, breast and uterine cancer
  • Mucocutaneous pigmentation - Strongly ssociated with mutations in STK11 gene which causes a condition called Peutz-Jeghers syndrome. This increases the risk of breast cancer and bowel polyps
19
Q

What decisions need to made on the assessment of families with multiple cancers or families with early onset cancers?

A
  • Is there an increased inherited risk of cancer?
  • How high is the risk?
  • Does the patient need genetic testing to look for mutations in high risk cancer predisposition genes?
    • Usually around a 1 in 10 chance of finding a mutation in a high risk cancer predisposition gene
  • Does the patient and/or their relatives need extra screening or other measures to reduce cancer risk?
20
Q

How would you manage the risk of inherited cancer in a person who you suspect has an increased multifactorial/polygenic risk of cancer?

A
  • Offer screening, prevention and early detection advice (SPED)
21
Q

What is chemoprevention?

A
  • Taking a medication to reduce risk of developing a particular cancer
  • Breast cancer: Tamoxifen/SERM (selective oestrogen reuptake modulater)
  • Colorectal cancer: Aspirin
22
Q

What are some of the disadvantages of chemoprevention?

A
  • Medication used have side effects of their own
  • Medication taken to reduce risk of breast cancer may cause menopausal symptoms, e.g. hot flushes, or in extreme cases may cause sexual dysfunction
23
Q

What things need to be considered before offering an individual genetic testing for high risk cancer predisposition genes?

A
  • Implications for individual
    • Recurrence risks
    • Risks of other cancers
  • Implications for relatives
    • ​How to share information
    • Concerns about children - high risk CPGs usually are inherited via autosomal dominant inheritance so greater chance of inheritance vai offspring
    • Family planning options (e.g. prenatal, PGD)
24
Q

What are the diferent types of tests used to identify high risk CPGs?

A
  • Diagnostic testing - To confirm whether a CPG has caused the cancer
  • Predictive testing - To identify if an unaffected person carries a CPG
  • NOTE: Don’t have to tell results of predictive test to insurance comapanies unlike with diagnostic testing
25
Q

What are the outcomes of a genetic test?

A
  • No genetic variant identified
    • Screening and management based on personal and family history
    • Referral for screening/further management only if personal + family history is significant
  • Disease causing variant in CPG identified
    • ​Screening and management tailored to specific CPG
    • Should be reviewed by NHS clinical genetics service
  • Variant of uncertain significance (VUS) identified
    • ​Considered benign until proven malignant
    • Referral for screening/further management only if indicated on above assessment
    • Need to explain to patient how common genetic variation is and that most VUS are benign to avoid anxiety in patient
26
Q

What are the differences between sporadic cancer and hereditary cancer?

A
27
Q

Somatic mutations are responsible for sporadic cancers while germline mutations are responsible for hereditary cancers, what are the differences between the 2 different types of mutation?

A
  • Somatic mutations
    • Occurs after division of the fertilised egg
    • Only present in some cells
    • Not inherited from a parent
    • Occasionally passed to offspring
  • Germline mutations
    • Present in the fertilised egg
    • Present in every cell in the body
    • Can be inherited from a parent
    • Can be passed to offspring
28
Q

What does the following family tree indicate about the risk of cancer within this family?

A
  • Shows early onset of breast cancer - 2 women have breast cancer at 37 and 38
  • Shows multiple types of cancer - breast and ovarian cancer (indicates presence of BRCA gene in family)
  • Lots of people in family have cancer - 5 people have breast/ovarian cancer
29
Q

What would you do after looking at this family tree?

A
  • Genetic test would be done on an affected person to see if they have CPG
  • Test would find BRCA2 mutation in affecetd individual
30
Q

What could be done after finding a BRCA2 mutation in affected individual within this family?

A
  • Offer treatment
  • Can offer treatment of risk reducing bilateral mastectomy
  • Can test unaffected sister for the BRCA2 mutation

Clinical pathology specialities: Clinical Genetics (5 decks)

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