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Path 19.06 notes > 19.06.04 Lynch syndrome and FAP > Flashcards

19.06.04 Lynch syndrome and FAP Flashcards

1
Q

Proportion of colorectal cancers (CRC) worldwide that are sporadic

A

85%

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2
Q

Proportion of colorectal cancers (CRC) due to lynch syndrome

A

3-5%

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3
Q

What genes are mutated in Lynch S

A

Mismatch repair (MLH1, MSH2, MSH6, PMS2.

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4
Q

Prevalence of Lynch syndrome

A

1/250 (most common form of predisposition to cancer)

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5
Q

Cancer types according to MMR genes

A
  • MLH1 mutations lead to GI cancers
  • MSH2 associated with a greater variety of cancers
  • MSH6 and PMS2- associated with reduced age-related penetrance.
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6
Q

Mean age of onset

A

45 years (often higher in MSH6 and PMS2)

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7
Q

Mutation spectrum in Lynch S

A

80-90% in MLH1 and MSH2, 7-10% in MSH6, <1% in PMS1/2.

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8
Q

What gene is upstream of MSH2, who’s 3’ end is deleted in 3% of cases

A

EPCAM

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9
Q

What happens when 3’ end of EPCAM is deleted

A

Creates a fusion EPCAM-MSH2 fusion. Leads to hypermethylation of MSH2 promoter and loss of MSH2 expression

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10
Q

Other genetic alterations in MMR genes

A
  • 10mb inversion on chromosome arm 2p, disrupting MSH2
  • A LINE-1 mediated retrotranspositional insertion in PMS2
  • Methylation of MLH1 promoter
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11
Q

What clinical criteria can be used in Lynch Syndrome

A
  • Amsterdam (developed to identify Lynch patients for research studies)
  • Bethesda guidelines (more sensitive but less specific than Amsterdam criteria)
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12
Q

Routine pre-screen testing in tumour samples for Lynch syndrome

A
  • Immunohistochemistry
  • MSI (microsatellite instability)
  • MLH1 hypermethylation
  • BRAF V600E
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13
Q

What is immunohistochemistry

A

Testing presence/absence of proteins in tumour slides using antibodies.

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14
Q

How sensitive is IHC for DNA MMR deficiency

A

95%

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15
Q

What are the MMR heterodimers

A
  • MSH2/MSH6

- MLH1/PMS2

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16
Q

Would we expect MSI if loss of MMR protein expression on IHC

A

Yes

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17
Q

When do you get normal IHC but MSI

A

-Missense mutations that result in a non-functional immunoreactive protein (5% cases)

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18
Q

What is MSI

A

Microsatellite instability. Genetic instability characterised by length alterations to microsatellites

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19
Q

How is MSI tested

A
  • Panel of 5 monomorphic markers assessed.
  • Comparison between tumour and normal tissue
  • 10-15% of sporadic CRCs have MSI
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20
Q

3 outcomes of MSI testing

A
  • Tumour has 2 or more altered mononucleotide markers = MSI high.
  • Microsatellite stable
  • One marker shows instability. Insufficient to be classed as instability associated with Lynch Syndrome.
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21
Q

What proportion of sporadic cancers have hypermethylation of MLH1 promoter

A

15%

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22
Q

Loss of MLH1 staining could be due to what

A
  • Somatic hypermethylation of MLH1 promoter (rarely germline)
  • 3’ EPCAM deletions
  • MLH1 mutations
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23
Q

What BRAF mutation is associated with MLH1 hypermethylation

A

V600E (Val600Glu)

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24
Q

What is BRAF

A

Oncogene

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25
Q

Does BRAF commonly occur in MSI high tumours

A

No, usually non-MSI high SPORADIC tumours

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26
Q

Why is BRAF V600E testing used as a pre-screen

A

Avoids unnecessary MMR gene screening

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27
Q

What proportion of MMR mutation carriers also have a BRAF V600E

28
Q

Issues with PMS2 sequencing

A

Has a pseudogene- PMS2CL

29
Q

What proportion of cases with MSH2 loss on IHC have EPCAM deletions

30
Q

Cancer types associated with EPCAM deletions

A
  • If deletion doesn’t involve MSH2 then cancers often restricted to GI tract (atypical for MSH2)
  • If deletion extends into MSH2 then behave phenotypically as MSH2 mutations
31
Q

Lynch syndrome testing strategy

A
  1. Tumour tissue checked for MSI and/or IHC of 4 MMR genes.
  2. Test tumour for methylation and or somatic BRAF mutations (are tumours more likely to be sporadic or hereditary)
  3. Molecular testing of MMR genes.
32
Q

NICE guidance on when reflex testing for Lynch syndrome is appropriate in newly diagnosed CRC patients

A

Under age of 50yrs

33
Q

What does DNA MMR apparatus do

A

Recognise errors in DNA replication (mis-incorporated bases, spillage of strands), that have been missed by DNA polymerase.

34
Q

Which MMR heterodimer preferentially repairs single base mismatch or mononucleotide repeats

A

MSH2-MSH6 (MutS alpha)

35
Q

Which MMR heterodimer preferentially repairs larger loop out errors (e.g. dinucleotide repeats)

A

MSH2-MSH3 (MutS beta)

36
Q

which MMR proteins are the dominant constituents of their pairs

A
  • MSH2 (with MSH6 or MSH3 to form MutS complex)

- MLH1 (with PMS2 or PMS1 to form MutL complex)

37
Q

MutS heterodimers require what other proteins to function

A
  • EXO1= excises the DNA between mismatch and adjacent nick

- DNA polymerase beta= resynthesises and repairs excised strand

38
Q

What is the reason for attenuated phenotype for MSH3/MSH6/PMS2

A

There is redundancy (if MSH6 is mutated then MSH3 can function)

39
Q

Treatment

40
Q

Prevention of primary manifestations

A
  • Colonoscopy

- Prophylactic removal of uterus and ovaries after childbearing is complete

41
Q

Steps in MMR

A
  • DNA polymerase misincorporates a nucleotide during DNA replication
  • MSH2-MSH6 heterodimer recognises and binds to the mismatch. ADP to ATP.
  • MLH1-PMS2 heterodimer recruited. ADP to ATP
  • PMS2 has latent endonuclease activity so nicks the daughter strand, 5’ to misincorporation.
  • Nick serves as an entry point for EXO1 exonuclease. EXO1 degrades a patch of daughter strand (including misincorporation).
  • Single-stranded gap in DNA is covered by RPA (single strand DNA binding protein) and filled by replicated DNA polymerase.
42
Q

-Patients with two germline variants have

A
  • Early disease onset

- Turcot syndrome. CRC and brain tumours.

43
Q

What are the revised Batheda guidelines

A
  • Tumours should have MSI testing if one or more exist:
    1. CRC in a patient diagnosed under 50yrs old
    2. Presence of CRC or other lynch-associated tumours.
    3. MSI high in CRC patient under 60yrs
    4. CRC in one or more first degree relatives (with a lynch tumour diagnosed under 50 yrs)
    5. CRC diagnosed in 2 or more 1st or 2nd degree relatives with lynch tumours (at any age)
44
Q

What is FAP

A
  • Familial adenomatous polyposis
  • Caused by APC gene mutations
  • Autosomal dominant
45
Q

What proportion of FAP cases are de novo

46
Q

How is FAP diagnosed

A
  • Presence of adenomatous colonic polyps

- Asymptomatic until adenomas cause rectal bleeding or anaemia, weight loss, change in bowel habits, abdominal pain.

47
Q

What is attenuated FAP

A
  • Fewer adenomas than FAP.

- Caused by mutations in APC, MUTYH and POLD1/POLE1

48
Q

What common extra-colonic manifestations occur in FAP

A
  • Fundic gland polyps (in stomach) in 90% cases
  • Thyroid cancer (1-2% lifetime risk)
  • 1% risk of pancreatic and liver cancer
49
Q

What is APC

A

Tumour suppressor gene

50
Q

What is the function of APC

A
  • In the Wnt signalling pathway, regulates beta-catenin degradation.
  • APC regulates the phosphorylation of beta-catenin, marking it for degradation by proteasome.
  • Presence of APC= degradation of beta-catenin
  • Mutant APC= accumulation of beta-catenin
  • Beta catenin target genes (e.g. c-myc) change proliferation/ differentiation state of cells.
51
Q

Does APC show genotype/phenotype correlation

52
Q

What is the APC mutation cluster that has 60% of known mutation

A

codons 1284 to 1580 (highest number of polyps and highest risk of CRC at a younger age)

53
Q

Where are variants that may cause attenuated FAP located

A

-5’, 3’ regions, exon 9

54
Q

Why are exon 9 variants associated with a milder phenotype

A

Exon 9 is alternatively spliced. Isoform without exon 9 is present in normal tissues. Mutations in this exon are spliced out.

55
Q

Why are 5’ variants associated with a milder phenotype

A

Truncating mutations in the first couple exons can escape NMD by undergoing translational initiation upstream (an internal ribosome entry site)

56
Q

Why are 3’ variants associated with a milder phenotype

A

Last exon of APC is large (>2000 amino acids). Nonsense variants in this region often escape NMD. Truncated protein functions partially

57
Q

Other types of APC mutations

A
  • somatic mosaics (11% of de novo cases)
  • APC promoter mutations. Deletions here may lead to gene silencing
  • Large deletions (8-12% cases)
58
Q

Presymptomatic FAP testing in minors

A

Colon and genetic screening offered from 10 years

59
Q

Treatments for FAP

A
  • Prophylactic colectomy

- Chemoprevention, cheap, effective, well tolerated. Can delay need for surgery

60
Q

What other gene causes FAP

A

MUTYH (autosomal recessive)

61
Q

What proportion of APC-negative colonic polyposis patients cases have MUTYH mutations

62
Q

What is MUTYH

A

A base excision repair gene

63
Q

What is the function of MUTYH

A

-MUTYH encodes a DNA glycosylase enzyme that excises misincorporated adenine bases caused by oxidative damage

64
Q

What type of mutation predominantly occur in MUTYH

A
  • Missense.

- p.Y179C and p.G393D account for 90% of all variants in N. European populations.

65
Q

Screening in MUTYH AP cases

A
  • Colonoscopies offered over 18 years.

- Genetic testing in children is not appropriate

Path 19.06 notes (29 decks)

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