MSH2

So Lynch is not a classic polyposis syndrome because patients do not develop hundreds of polyps, but it is a major hereditary colorectal cancer syndrome and an important contrast to FAP.

So Lynch syndrome results from mutations in DNA mismatch repair genes, including the MLH1, MSH2, MSH6, and PMS and PMS2.

Patients may only have a few adenomas, but the progression from adenoma to cancer can happen more quickly.

Think early onset and often right-sided colorectal cancer, plus a family history of endometrial, ovarian, gastric, urinary tract, or other related cancers.

I'd just been involved in proving that folic acid prevents spina bifida in pregnant women who'd had previous babies affected with spina bifida.

and it seemed like an obvious thing to try interventions that might prevent polyps in these kids not only for them but also for us because our colon cancers also are driven by APC mutation very often so that seemed like an easy idea but it turned out to be quite challenging in 1993 we got all of the European centers together and got the money to launch in that year the CAP1 what became CAP1 And as it happened in that year, we were involved with Richard Fishel and Rick Kolodner in Boston, helping to identify the MSH2 gene in one of our big families.

Of course, I immediately realized we'd picked the wrong disease.

So the concept of genetically targeted trialing or precision prevention, as it's now called, was clearly a good one.

OK, it may be you don't carry the gene, but if you took aspirin for five years, so what? You know, I mean, I mean, it actually works for everyone a little bit.

And so I would argue that it's actually a great way of avoiding the debate about gene testing if you don't want to do it.

If you say if you'd rather not test the kids, just put them on aspirin at 20, if they're going to MSH2 and MH1.

and then wait until they're 25 to do the DNA test to decide whether they need the invasive, life-threatening investigation of colonoscopy.

The typical MMR evaluation, MLH1, PMS2.

MSH6, MSH2.

When there's loss of expression, that means there's an abnormality.

We're going to talk about the therapeutic implications, but we also could talk about the, it's also a triage tool for germline mutational status for those patients with Lynch syndrome.

And that leads to more mutations, which can give rise to cancer.

So that's the premise of cancer for the majority of the time, the cancer predispositions that we're talking about, the The risk syndrome results from having one non-functional copy and not having a backup copy of that gene, for example, p53 or BRCA2 or MSH2 or the Lynch genes.

And if you were to take somebody who had an inherited BRCA2 mutation, for example, they would have one functional copy and one maybe non-functional copy, but they can get through life with just the one functional copy, but they're one step closer.

But if you look then at their cancer, let's say they developed prostate cancer, and it was a high-risk prostate cancer, high-grade Gleason, let's say Gleason 9 or grade group 5 cancer, and then you looked at the DNA or you did somatic or genomic testing, tumor testing, you would also find the somatic mutation as well as the original germline mutation.

Okay

... are the proteins MSH2 and MSH6, coded for by the genes MSH2 and MSH6.

Mm-hmm.

Now, here's what matters for you.

Okay.

The reason that matters is because Lynch syndrome is actually caused by genetic changes in multiple different genes.

MSH2 and MSH6 are on that list.

Okay.

menstruating to stop my period, which did help a little bit with the endometriosis as well.

But because there was an MSH2, which is a genetic flag for an endometrial cancer or a colon cancer, my gynecologist and my oncologist decided that a hysterectomy was the best path forward.

And it was mentioned that I'd go into acute menopause That was it.

That was the mention.