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Molecular Basis of Disease - SGUL (Sem 4) > Clinical Cancer Genetics > Flashcards

Clinical Cancer Genetics Flashcards

1
Q

What mutations can occur to cause cancer

A
  • Constitutional (germline)
  • Somatic
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2
Q

What are the characteristics of Constitutional mutations?

A
  • Hereditary
  • Informs future cancer risk
  • Informs treatment decisions
  • Provides information for other family members
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3
Q

What are the characteristics of somatic mutations?

A
  • Acquired
  • Informs treatment decisions
  • Provides reassurance for family and future children
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4
Q

What is the common architecture of genetic susceptibility to cancer

A
  • Sporadic 65%
  • Familial Cancer 25%
  • High risk cancer genes 10%
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5
Q

Explain the architecture of inherited cancer predispositions

A
  • Very rare mutations have the highest cancer effect and common mutations cause the least cancer effect
  • Some exceptions are highly common mutations causing high-effect cancers and vice versa.
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6
Q

What are the characteristics of 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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7
Q

Why do we identify patients with increased genetic predisposition to cancer

A
  • Informs medical management and surgical options
  • Inform relatives about cancer risk - access to screening
  • Provides reason for why cancer developed
  • Informs patient about future risk
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8
Q

How can we identify patients with increased genetic predisposition to cancer

A
  • Family History
  • Pathology of cancer
  • Syndromic features
  • Tumour testing
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9
Q

What do we look for in a family history assessment

A
  • Bilateral cancer or multiple cancers in the same individual
  • Young age of onset
  • Multiple cancer diagnoses of the same type in related indivaduals
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10
Q

What methods have been developed to track cancer family history easily

A
  • Apps to enter cancer history and family history
  • Easier to enter for the patient and results can be viewed and manipulated digitally
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11
Q

What are polygenic risk scores

A
  • Genetic testing of multiple low risk factors
  • Not currently performed on the NHS
  • Can indicate increased genetic susceptibility to
    cancer
  • Undertaken by looking for cancer associated
    SNPs found from Genome Wide Association
    Studies
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12
Q

How can we use GWAS to find cancer-causing gene’s

A
  • Look for cancer-associated SNP’s
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13
Q

How can we assess histopathology and cancer predisposition genes

A
  • Certain genes are associated with specific cancers
  • Refer to lecture slide
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14
Q

What syndromic features can associate with cancer

A
  • Trichilemmoma
  • Mucocutaneous Pigmentation
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15
Q

How can we tumour test for germline cancers

A
  • Cancer patients now being offered large
    cancer gene panel sequencing of their tumour
  • If we find a disease causing change in a cancer
    predisposition gene on testing the tumour, it is
    possible it might also be in the germline
  • We can then offer a blood test to check this
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16
Q

What is stratified prevention?

A
  • Categories population into risk groups for cancer
  • Appropriate interventions for each stratum
17
Q

Summarise Multifactorial/polygenic risk assessment

A

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
18
Q

Should we test for high risk CPGs

A
  • Likelihood of finding a pathogenic variant is more than 10%
  • Test according to NHS guidelines for who we can test
19
Q

How is cancer predisposition nearly always less than 100%

A
  • Not everyone with altered genes inherits and exhibit cancer
  • Other factors at play such as environmental factors
20
Q

Explain cancer predisposition gene inheritance

A
  • Most inherited cancer predispositions inherited in autosomal dominant fashion therefore 50% chance of passing on to child (male or female)
  • Occasionally, autosomal recessive predisposition to cancer can occur, with healthy carriers but when a child inherits 2 pathogenic variants (e.g. MUTYH gene, there is a predisposition to 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 anaemia gene, ATM = ataxia telangiectasia
21
Q

What order do we do genetic testing

A
  • single gene
  • NGS panel
  • WES
  • WGS
22
Q

What are the outcomes of diagnostic genetic testing

A
  • No disease-causing variant identified
  • Variant of uncertain significance identified
  • Disease causing (pathogenic) variant identified
23
Q

what happens if a clinically actionable pathogenic variant is found in CPG

A

Manage according to gene-specific protocol

Screening, Prevention and Early Detection (SPED) e.g:

  • Non-invasive imaging –often more frequent and starting at younger age
  • Invasive – often more frequent, starting at younger age
  • Chemoprevention
  • Risk reducing surgeries
24
Q

what is Predictive testing

A
  • A test in a WELL 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
25
Q

What are the most frequent causes for hereditary breast cancers

A
  • BRCA1 and BRCA2 genes
  • PALB2, ATM, CHEK2, RAD51C, RAD51D
  • Account for ~20% of familial breast cancer
  • Contribution to overall breast cancer ~5%
  • Involved in DNA repair and regulation of transcription
  • Disease-causing (pathogenic or likely pathogenic) variants result in an increased risk of developing certain cancers
  • Founder mutations common in specific populations e.g. Polish, Ashkenazi Jewish
26
Q

What is Lynch Syndrome

A
  • Prevalence: 1 in 400
  • Accounts for ~1-3% of all CRCs
  • Mismatch repair
  • MLH1, MSH2, MSH6 and PMS2

-Disease-causing (pathogenic or likely pathogenic) variants result in an increased risk of developing certain cancers:

  • Particularly colorectal, endometrial and ovarian
  • Other LS-associated cancers: small bowel, gastric, brain, ureter, renal pelvis, hepatobiliary, pancreatic and sebaceous skin tumours
27
Q

How is Lynch Syndrome inherited?

A

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
28
Q

How is Lynch syndrome screened and managed

A

Screening:

  • Colorectal
  • Symptom awareness

Risk-reducing surgery:

  • Hysterectomy +/- BSO

Chemoprevention:

  • Daily aspiring

Research

Cancer management

Reproductive options

Molecular Basis of Disease - SGUL (Sem 4) (29 decks)

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