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Molecular Basis of Disease(Sem 4) > Clinical cancer genetics > Flashcards

Clinical cancer genetics Flashcards

1
Q

What are the two types of mutations that occur in cancer ?

A

Constitutional (germline ) mutations

Somatic mutations

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2
Q

What are germline mutations ?

A

Hereditary
Informs future cancer risk
Informs treatment decisions
Provides information for other family members

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3
Q

What are somatic mutations ?

A

These are acquired
Informs treatment decisions
Provides reassurance for family and future children

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4
Q

What are the three types of cancer patients ?

A

Sporadic cancer
Familial cancer
High risk cancer

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5
Q

What is the multifactorial /polygenic familial risk ?

A

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)

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6
Q

How do the high risk cancer predisposition genes depend on cancer types?

A

Breast cancer5-10%

Colon 5-10%

Prostate5-10%

Ovarian 10-15%

Melanoma10%

Pancreatic10%

Medullary thyroid25%

Retinoblastoma40%

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7
Q

Why do we try to identify patients with increased genetic disposition to cancer ?

A
  1. Informs medical management and surgical options .
  2. Provides reason for why developed cancer
  3. Informs patients about future cancer risks
  4. Informs relatives about cancer risk-access to screening /risk reducing surgery
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8
Q

How can we identify patients with increased genetic predisposition to cancer ?

A

Family history
Syndromic features
Tumour testing
Pathology of cancer

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9
Q

Outline family history assessment

A

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)

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10
Q

What are polygenetic risk scores?

A

Single value estimate of an individual’s genetic liability to a trait or disease.
Target to look at specific changes using SNP from GWAS

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11
Q

What are syndromic features?

A

Very rare cancer predisposition genes
Flags on clinical examination

  • Trichielomma
  • Mucocutaneous pigmentation
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12
Q

What is stratified prevention ?

A

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

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13
Q

What is Tamoxifen?

A

This is an anti-oestrogen drug which has been shown to reduce the risk of woman developing breast cancer when coming from family’s with increased suceptibility to breast cancer - Chemo prevention

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14
Q

Give a summary of multifactorial /polygenic risk assessment

A

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
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15
Q

When is testing offered to patients for high risk cancer predisposition genes ?

A

Where there is a likelihood of finding a pathogenic variant is greater than 10%

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16
Q

What are the caveats of cancer predisposition genes ?

A

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.

17
Q

Describe cancer predisposition inheritance

A

Most inherited cancer predispositions are inherited in autosomal dominant fashion therefore 50% chance of passing it on to child

18
Q

Outline autosomal recessive cancer predisposition inheritance

A

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 predispositions are linked to autosomal recessive conditions in rare cases when biallelic pathogenic variants are inherited e.g.BRCA2 is a Fanconi anemia gene

19
Q

What are the different genetic tests which are offered ?

A

Single gene

NGS panel
(Next generation sequencing)

WES
(Whole exome sequencing )

WGS
(Whole genome sequencing )

20
Q

What are the outcomes of diagnostic genetic testing ?

A
  1. No disease causing variant is identified
    - manage on basis of family history and personal diagnosis
  2. 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 .
  3. Disease causing (pathogenic) variant identified
    - manage as per gene specific protocol
    - Can offer cascade screening to relatives
21
Q

What would happen if a actionable pathogenic variant is identified?

A

Screening, Prevention and Early detection

  • Non invasive imaging -more frequent from a young age
  • Invasive-more frequent
  • Chemoprevention
  • Risk reducing surgeries
22
Q

What is predictive testing ?

A

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

23
Q

What are the genes which are most frequent monogenic causes for hereditary breast cancer ?

A

BRCA1 / BRCA2 genes
-They account for 20% of familial breast cancer
Contribution to overall breast cancer
-Involved in DNA repair and regulation of transcription
-Disease causing variants result in an increased risk to develop certain cancers
-Founder mutations common in specific mutations e.g Polish

24
Q

What is the carrier management ?

A

Screening
Risk reducing surgery Chemoprevention for BRCA2 carriers
More BRCA2 carriers recommended to have annual PSA test

25
Q

What is Lynch syndrome ?

A

This is a familial colorectal, womb and ovarian cancer which is 1-3% of all cancers.
Caused by mismatch repair in (mutations )
MLH1,MSH2,MSH6 and pMS2.

26
Q

How are patients checked for Lynch syndrome ?

A

A tumour test is offered to find four proteins produced by the genes .

The cancer risks are dependent on the gene and gender of the patient

27
Q

What is some further lynch syndrome carrier management

A

Screening:

  • colorectal
  • gastric
  • symptom awareness

Risk reducing surgery:
Hyseterectomy +/- BSO

Chemoprevention
Low does aspirin

Research
Cancer management
Family matters

Molecular Basis of Disease(Sem 4) (28 decks)

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