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.
