Mismatch repair deficient cancers diagnosis, treatment and prevention

Published on September 3, 2014   44 min

Other Talks in the Series: Molecular Genetics of Human Disease

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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Mismatch repair deficient cancers diagnosis, treatment and prevention

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