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- Genetics of Developmental Disorders
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1. Imprinting disorders associated with molecular changes on chromosome 11p15
- Prof. Rosanna Weksberg
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2. Chromatin genes and disease
- Prof. Richard Gibbons
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3. Heterochromatin, epigenetics and gene expression
- Prof. Joel C. Eissenberg
- Cardiopulmonary Disease
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4. Transcription factors and complex disease development
- Dr. Ines Pineda-Torra
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5. Molecular genetics of pulmonary arterial hypertension
- Prof. Richard C. Trembath
- Neuromuscular System Diseases
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6. Gene therapy for the muscular dystrophies
- Prof. Jeff Chamberlain
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7. RAS pathway and disease: neurofibromatosis and beyond
- Prof. Eric Legius
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8. Congenital syndromes of pain and painlessness
- Prof. Geoff Woods
- Prof. James Cox
- Endocrinology and Metabolism
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9. Changing lives: stratified medicine in monogenic diabetes
- Prof. Andrew Hattersley
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10. Genetics of monogenic obesity 1
- Prof. Dr. Johannes Hebebrand
- Prof. Dr. Anke Hinney
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11. Genetics of monogenic obesity 2
- Prof. Dr. Johannes Hebebrand
- Prof. Dr. Anke Hinney
- Cancer Genetics
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13. Inherited predisposition to breast cancer
- Prof. Diana Eccles
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14. Genetics of breast and ovarian cancer
- Prof. Jeffrey Weitzel
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16. NF2-related Schwannomatosis and Gorlin Syndrome
- Prof. D. Gareth R. Evans
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17. The genetic basis of kidney cancer
- Dr. W. Marston Linehan
- Oligogenic and Complex Diseases
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18. Ciliopathies and oligogenic phenomena
- Prof. Nicholas Katsanis
- Therapy
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19. Mismatch repair deficient cancers & Lynch syndrome
- Prof. Sir John Burn
- Archived Lectures *These may not cover the latest advances in the field
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20. Mismatch repair deficient cancers: diagnosis, treatment and prevention
- Prof. Sir John Burn
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21. NF2 & Gorlins
- Prof. D. Gareth R. Evans
Printable Handouts
Navigable Slide Index
- Introduction
- Lynch syndrome
- Lynch syndrome: underlying single gene defect
- Microsatellites
- Important genes containing repeat sequences
- MSI testing - 5 marker panel
- MMR immunohistochemistry
- The genomic pathogenesis of colorectal cancer
- EGFR and BRAF mutant inhibition
- Timeline of BRAF colon cancer project
- Methotrexate & mismatch repair deficient tumours
- Africans don’t get bowel cancer', Dennis Burkitt
- CAPP
- NSAIDs and reduced colorectal cancer risk
- Observational studies of NSAIDs and CRC
- CAPP factorial design
- Aspirin reduced polyp size in 200 FAP carriers
- Aspirin reduced the risk of a colorectal adenoma
- The prevention paradox
- 43 CAPP2 recruiting centres
- 600mg aspirin for up to 4 yrs
- A trend to reduced CRC in aspirin group
- Intention to treat analysis of CRCs (follow-up)
- CAPP2 primary endpoint
- CAPP2, significantly fewer colorectal cancers
- CAPP2, all Lynch syndrome cancers
- Aspirin for 2 yrs reduced Lynch syndrome cancers
- CAPP2 follow up data, May 2013
- Meta-analysis: less cancer deaths in aspirin group
- Alternate day 100mg aspirin: fewer CRC at 10 yrs
- CRCs in people on aspirin: mostly COX2 negative
- Individual response to aspirin in cancer prevention
- History of salicylate
- Salicylate as an essential nutrient
- CAPP3 study (1)
- CAPP3 study (2)
- Slippage in coding microsatellites creates peptides
- Abs seen in Lynch syndrome: possible biomarker
- The Micoryx vaccine
- Summary: aspirin prevents cancer
- Acknowledgements
Topics Covered
- Lynch syndrome (underlying single gene defect)
- Microsatellites
- Important genes containing repeat sequences
- MSI testing (5 marker panel)
- Mismatch repair (MMR)
- The genomic pathogenesis of colorectal cancer (CRC)
- EGFR and BRAF mutant inhibition
- BRAF colon cancer project
- Methotrexate & MMR deficient tumours
- Africans & bowel cancer (Dennis Burkitt)
- Cancer prevention program (CaPP)
- NSAIDs and reduced colorectal cancer risk
- Aspirin effect on polyps in FAP and colorectal adenoma
- The prevention paradox
- CaPP2 (Colorectal & Lynch syndrome cancers)
- Meta-analysis of cancer deaths with aspirin treatment
- CRCs in people on aspirin (mostly COX2 negative)
- Individual response to aspirin in cancer prevention
- History of salicylate as an essential nutrient
- CaPP3 study
- Peptides created by slippage in microsatellite coding
- Antibodies as a possible biomarker for Lynch syndrome
- The Micoryx vaccine
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Burn, J. (2014, September 3). Mismatch repair deficient cancers: diagnosis, treatment and prevention [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 14, 2024, from https://doi.org/10.69645/GROL9065.Export Citation (RIS)
Publication History
Financial Disclosures
- Our CAPP1, CAPP2 and CaPP3 trials have been supported by Bayer Pharma who provided aspirin and placebo tablets and supported packaging costs. I am named on the patents for the Newcastle MSI-Plus assay. This was first supported by a PhD studentship funded by biotechnology company QuantuMDx ltd. The company will receive a profit share if the University succeeds in commercialising the assay. I currently chair QuantuMDx and hold shares in the company.
Mismatch repair deficient cancers: diagnosis, treatment and prevention
A selection of talks on Cell Biology
Transcript
Please wait while the transcript is being prepared...
0:00
My name is John Burn, and I'd
like to talk about mismatch repair
deficient cancers, their
diagnosis, their treatment,
and their prevention.
0:11
Back in 1993, Richard
Kolodner's group
were the first to describe
mutations in the MSH2 gene
and one of the mismatch repair genes
in a family with hereditary cancer.
In fact, there were two
families that they looked at.
And one of them was sent
by us from Newcastle.
Ted was a shepherd in Berwick and
he'd had colon cancer three times
and nine skin cancers.
And his sister Bertha had
an endometrial cancer.
And all the people shaded
yellow in this slide
had developed many bowel cancers.
And in fact, one of that
girls on the bottom line
had developed bowel
cancer at the age of 18.
We had identified this gene
as being on chromosome two.
And Richard was keen to look at a
family with hereditary nonpolyposis
colon cancer because it has been
observed by the overseeing group
that the tumors in these patients
had lots of spelling errors
in the DNA.
And Kolodner's group correctly
deduced that this might mean
a problem with this
mismatched repair.
1:09
Rolling forward now
into the 21st century,
we know that hereditary
nonpolyposis colon cancer,
or Lynch syndrome as it's
now called by most people,
is one of the commoner
rare diseases.
And it probably accounts for between
3% and 5% of all colorectal cancers
and a similar proportion
of endometrial cancers.
This rather nice breakdown is
useful for the non-specialists,
put together by the Toronto team.
So if one took 100 colorectal
cancers, a roundabout of 15 of them
would show microsatellite
instability,
or MSI high, which means
that repetitive bits of DNA
are not copied
accurately and you get
multiple versions of the original.
If you look among those 15
microsatellite unstable tumors,
typically 13 of them would be due
to a sporadic silencing of the MLH1
gene, but two of them would be
the HNPCC, or Lynch syndrome,
due to a germline defect in one
of the two genes, MLH1 or MSH2.
A small proportion are also caused
by mutations in a MSH6 or PMS2.
And that's because these four genes
play a pivotal role in DNA repair.
There's a very useful summary
of our clinical assessment
of this syndrome published by our
colleagues from the Majorca group
with Hans Vasen as first author.
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