 So, y gweithio. Thank you very much for the invitation. I very much enjoyed this meeting. For those of you who don't know me, which I think is pretty much everyone, I'm predominantly a researcher. My group identifies genes that predispose cancer. I'm also a clinical geneticist and I run the cancer genetic service at the Roym Marsden Hospital. And I'm really going to speak to that today. We are particularly passionate about trying to realise a wnaeth eich cyfnodau wahanol mewn cyfnodau newydd i gynhyrchu eu ddweud o bobl o'u cyfrifiadau i ddweud i'r llyfr y lleidion llawm. Felly, i wnaeth eu cyfrifiadau yma, rwy'n amdano i'r cyfrifiadau yn y cyfrifiadau yma, yna gydag hwnnw ymddangosiaethau oherwydd mae'r cyfrifiadau cyfrifiadau yn ydych chi'n gweld i'r cyfrifiadau. Felly, rwy'n amser, felly rwy'n gydag o'r cyfrifiadau i ddweud i'r clywed. Felly, dyma'r rheoli y gallwn gweld, sy'n gweld, gweld yn ym Oaf fynd yn dod nifer 15 yno, sy'n gwybod y rhain oedd, a phrofiadau yng Nghymru sydd wedi gynnig o hyd o gwybod o fwy'r fwy yr ysgolig clwnifidol gyda'r llagneu ac oedd cyntaf iddyn ni'n gwybod dim ydych chi'n ffordd i'w gwaith y maen nhw'n cweithio o'r sefyllfa'r höllunol yn y rhagor a'r bais抽 wrth gofyn i'r holl. A'r adnod ein bod ydsigol gyda cyfrifau a sír a'r ddysgwys ymddangos yn y dyfodol. Rydyn ni'n credu'r graff yw'r gweithio'r ysgolodio'i gael ar yr unrhyw sydd wedi'u cymunedol yn cael ei ddweud o'r droswm o'r gwneud hwnnw, yma'r ddweud yw ddweud yma eich 24 cymrydau sy'n ei ddweud ar gyfer gyfwilol. Mae'r droswm wedi'u cyfrifio'r gyfrifio'r ddweud, yn cael esganol o'r ddweud o'r ddweud o'r cyfrifio'r ddweud, y rhaid i'r gen i rywun o'r tudwg. Rwy'n gallu Llywodraeth i'r rhaid, oes e'ch cynnig, ond bydd am y 내wn y rhaid, a buddwyl sydd sy'n rhaid i'siolio, i'r rhaid o microbiol rhaid i'r run i'r mynd i'r bwyd. Maen nhw'n mynd i'r rhaid i'r rhysgu honno 10 o 15 o'r ffordd, rhaid i'r rhysgu o arall o dwyled o'r llifn honno gynol. Y ddefnyddio gynhyrchu hefyd yn ystod ar hyn o'ch mysensio ffairianysau i'r busau. Rydw i'n debyg ar gyfer y lliwyddiadau i'r rhaglen ychydig. Y dyfodillrwy'r gynhyrchu hefyd yn ddoddogf yn gweithio ar gyfer ond y cysyllt ddwych yn rhan, ychydig ar gyfer y gynhyrchu ddwych yn rhan o'r 2,000 o gynhyrchu ddwych yn llunio ar gyfer ond y cyflnwys. When you do that kind of experiment for this type of gene, there's a very clear signal between your cases and controls with respect to truncating mutations. But when you look at the miss-sense mutations, the data is really quite interesting. So you will always see multiple, rare, usually singleton, miss-sense mutations that are only present in your cases. These are just the type of miss-sense variants that are called V攝s, or in gene discovery papers where controls are not analyzed, be cyfnodd yn fwy oedd yn fathogennu fel ydych chi'n meddwl i gydag i'w cwysbeth fyddwch. Ond, ond, y gallu gwladwch y ddweud o ddweud y gydag, ac ond sy'n gydag i ddweud i'w cyfnodd a dwi'n meddwl i'r ddweud o ddweud o'r ddweud mae'r ddweud y ddweudio, mae'r ddweud o ddweud o ddweud o'r ddweud o ddweud o'r ddweud. Ond, ifn cwysbeth a chael fwy o'r ddweud o ddweud a amddwn ni'n dweud â'i nowa, a mae hwnna'n gweld, oherwydd mae'n meddwl yn ystod y gweithio bod yw'r gweithio yn nad o'r bwysig o'r bwysig oherwydd gan hyn o'r cyfrifoedd, o'r cyfrifoedd o'r cyfrifoedd, o'r cyfrifoedd o'r cyfrifoedd, o'r cyfrifoedd o'r cyfrifoedd o'r cyfrifoedd o'r cyfrifoedd. Mae'n ddysgu'n gwybod fwy o'r wladau. O'n fwy o'n fwy o'n fwy o'r bwysig o'r cyfrifoedd? Y ffordd, mae'n cyd-ddefnyddio am ymddîm gallu tynnu … … a'r ddrifogolod. So, mae'n trefwg hynny yn gweithio'n ddylu o hyd … … ac mae'n ddifogol ar yMyth-Centh ac ar gweithio'n ddylu ac … … mae'n ddifogol ar gyfer araf amddîm hynny a ddifogol gweithio'n ddylu. Mae'n ddifogol ar gyfer ar gyfer tyg amddym hynny … … oeddi'r ddifogol ar gyfer gweithio gweithio gweithio gweithio. is often assumed to be the same as pathogenic, just isn't. It's incredibly difficult to pick out disease-causing mis-sense mutations even in genes which we know cause disease. I think the bottom line is that buses should be considered and we consider them as innocent until proven guilty. I think that everybody does know that when you talk about it, but actually instinctively a lot of people, even the most expensive fields, are actually when they see those variants, they actually manage them as guilty until proven innocent. I think that that's a problem. With respect to clinical utility, we're not using the GWAS common variants and I don't think that we'll be doing that in a meaningful way anytime soon. With respect to these intermediate penetrance genes, I think once sequencing makes that cheap and quick, we will be able to use them. But BRCA 1 and 2 is clinically usable and in many ways offers all that you could hope for from a disease gene. I think with respect to unaffected women, people are very on top of this and they understand this, these women are at high risk of breast cancer, ovarian cancer, we give them increased surveillance. They will often have their ovaries removed after completing their family and many of them will also have bilateral mastectomies. I think surprisingly it's underappreciated just how important and how helpful it is to know the BRCA status in somebody who has cancer. If you have breast cancer and you're BRCA positive, you're at high risk of having bilateral breast cancer, you're at high risk of having ovarian cancer, increasingly there are genetic tailored treatments such as PARP inhibitors which are close to being in widespread use that are tailored to that genetic defect. This is making a sizeable contribution to this cancer incidence. So if you take unselected ovarian cancer just walking into the clinic, over 10% of those will have a BRCA mutation and all of those are at high risk of breast cancer if nothing else. It's a smaller proportion of unselected breast cancer though in certain subgroups such as triple negative it's over 10%. I would certainly like to see and what I hope the new technology will allow us to do is to offer BRCA testing to all women with breast and ovarian cancer. So what are the challenges to the implementation of that? Well, we need cheap quick testing and this should be achievable. Obviously there's also the issue of patterns which I'm not going to talk about today, partly because I'm not able to talk about it unless I've junked quite a lot of gin. So I'm assuming that that bit will be solvable. We need to have quick, simple report of the results and that will have to be readily understandable by non-genetic experts and we will need that to be then triaged into what the clinical actions should be. So where are we with that? We're a long way off from that. So we saw this slide yesterday from Les. This is one of the ways in which classification systems for BRCA variants are used. We don't use this. Why don't we use it? I think there are a number of different problems. It is a fairly arbitrary system based on various assumptions. That sounds like criticism. I don't mean is it criticism. I think that taking your best guess is the bedrock of clinical practice and science. I don't have any problem with that. I'm not sure that if you are guessing that you should quantify that to three decimal places. And I think that if you are having an arbitrary pragmatic system you should try and have it as simple as possible and it should be tailored to the aims you're trying to achieve. I think this is very laborious and many variants you just don't have the data in order to classify it. But I think the main problem is there are five variant classes but there are effectively only two management things. You either can manage it as a positive or a negative. And therefore, if you're trying to have this system you have to be able to tailor that into your management strategy. So I get daily emails, I think, from people around the world where they've got variants that are in classes two, three and four and they don't know what to do about them. And again, going back to these things that most people sort of think of things as being guilty until proven innocent, there have been hundreds of women who have had their breasts removed on the basis of variants that are highly, highly likely to not be increasing their risk of breast cancer. So in part to manage my inbox and in part because we wanted to think about trying to make this more user-friendly. Over the last year we've been using a different system and this is a system that we use. So we have a variant category but it's very much tailored towards going to a management category and in the management category it's either negative or it's positive. And I think the key difference, which was a slight moment of epiphany in my group, I think, was that instead of trying to classify every variant individually, there is a default category that when you first have a variant if you can't do anything else to it, it goes into what we call our variant two category. So if there's a mis-sense variant that's never been seen before, you actually can't move it into pathogenic, you can't move it into four and that just goes straight, that's into and it goes straight out to getting our report. If a variant has been seen before and has been previously categorised, obviously it goes into that category. If a variant is a frame-shifting mutation, you can just code that, that will go straight into pathogenic because we know that it doesn't matter whether you've seen it before or not, if it's causing premature protein truncation, it is pathogenic. And then we have, the possibly assignable is for the group where there is some information in the literature but or available but it's not sufficient to say it's pathogenic and here we're using genetic information because at least for the BRCA genes there is no robust in-silico predictive information or functional information unless it's showing that it's the equivalent to a frame-shifting mutation that will allow you to call that pathogenic. So those are the categories that we use. This is, following Howard's example, this is one that I did this morning because I had one in my inbox. So this is a variant here which has not been reported before. In fact, the in-silico predictions and conservation wouldn't suggest that it was pathogenic and so that goes straight out to our variant too and this is what those reports say. Managers are negative BRCA tests. The consultee should be informed that the BRCA test was negative. I think the next bit would be a point of discussion, possibly a point for transatlantic difference. A discussion of the variant is not required. There's a management recommendation. Breast surveillance should be recommended appropriate to family history and we have, that goes to a protocol. We have a number of protocols on there. The only rule of thumb is that no protocol can be more than one page. No predictive testing should be offered for this variant. No additional analyses are currently required. So is this model transferable or scalable? I think it probably is both. At the moment our reports are going back to geneticists or genetic councillors because those are the people who are doing those tests but I can see how it could go into oncology. If the oncology people were doing the tests, the negatives would just be negatives. In terms of the positives, the report would be slightly different. You'd have the information that the oncologist potentially would be using and then there would be another thing that would say refer to genetics. So here, instead of genetics having to see everybody, we're seeing the positive people. We will do the genetic information. We will be doing the cascading and we can manage that in terms of ours. What we can't manage is seeing everybody who's going to be negative. I think there probably are other genes and systems for which it is also transferable. We often would ask what you need, what I would really like. I said yesterday, I think we need more data. I think we need population data. One of the major areas where we're doing mismanagement is when you've seen a variant that's been seen in cases from a particular ethnic group. It's assumed to be pathogenic because it's been seen several times from a particular ethnic group but the equally plausible and I would say more plausible thing is that that is a population-specific polymorphism. Unless we have really good data on these low-hanging fruit key genes from lots of populations, we are going to keep making that mistake and I'm not clear that we're just going to get that data unless we directly try and get it. I think it also does give you better information about the spectrum of mutations across there and because BRCA1 and 2 are old genes, there's virtually no sequence data from control individuals and BRCA1 and 2 because it was sort of done before. It's still quite a herculean enterprise but it certainly was then. We clearly need much, much better predictive in silico methods that's a given. What I'd really like to see is some standards for deciding, for us as a group or some group, to decide if genes or variants are definitely pathogenic. So really thinking about which ones were classifying into that group. I appreciate that all the others we need to sort out as well but at least if we can sort that out. I want to just finish on a sort of caution retail to exemplify that. So RAV51C was a gene that was published in nature genetics, very high profile about 18 months ago and it was published as a high-penisurance breast ovarian gene comparable to BRCA1 and 2. It's got anomim entry, BRCA3. I'm aware of at least one woman who's had prophylactic mastectomies because they have a mutation. It was a little unusual, this paper, because in it truncating mutations are only found in breast cancer cases if they were in families with both breast and ovarian cancer. If you looked at families with just breast cancer only, there were no mutations and that's obviously odd for a high-penisurance breast cancer gene. Subsequent data, nobody was finding any truncating mutations but they were finding mis-sense mutations. They thought, alright, the mis-sense mutations are causing breast cancer. That wasn't the original hypothesis and no controls were studied. For a variety of things I haven't got time to go and we were working on another gene which is an ovarian cancer gene. Anyway, we've looked at this and this is hopefully shortly going to be published but it is also consistent with all of the available data including the original paper, I should say. So we did a large case of control resequence suddenly looking at both cases and controls. RAV51C is an ovarian cancer gene. It has a decent size risk of ovarian cancer, about 9% lifetime risk, but it doesn't predispose to breast cancer. So what's going on? I think it's fairly old-fashioned ascertainment bias. If you've got a gene that causes phenotype A, in this case ovarian cancer, and you look at phenotype B, which is breast cancer in this case, but the only breast cancer cases you're looking at are relatives of your phenotype A. You are bound to see an association unless you correct for that. But if you look at phenotype B on its own, which they did, you're not going to see an association. So 18, 24 months after that first gene report, you know, the cancer risks are clarified, it's not a high risk breast cancer gene, in fact it doesn't cause breast cancer. But you can see a potential where if we'd had the whole genome data in the electronic patient records, and that data was already available and the gene comes out, you're thinking, right, it's high risk breast cancer, you can see there's a situation where a lot of women might have thought, right, I'm going to have prophylactic surgery or act on that. And I think we're in an era where there's going to be lots and lots of new gene discoveries. When you're writing a paper, it is perhaps natural that one's optimistic about the clinical utility of that. And there's often in that paper, but I think there needs to be standards or principles by which people can look to see whether it has passed a bar where it is ready to be used in the clinic. And I think we need to think about that now, and I'll finish then. All right, I think we used up our question time. Sorry, unless somebody has. Heidi, do you have a quick one? Just a quick question. You mentioned recommending no management in cases where there's a not assignable BRCA1 variant. You know, we study cardiomyopathy, which is a very similar paradigm in terms of dominant inheritance and high risk for sudden cardiac death and a need to manage those family members. And we would always recommend familial testing to look at segregation in order to determine the clinical significance of those VUSs. And once you get a high enough LOD score, you can say with statistical confidence that that variant is pathogenic and then use it in a predictive fashion. So I'm a little bit concerned about not encouraging those physicians to pursue familial studies, which can be extremely informative in terms of pathogenicity. So I think that with respect to those class three ones, we certainly do do that. All the class three ones, we then would recruit into our research and we would do that more broadly. I think this does speak to things, what should you do with just any VUS? And it then also speaks to the fact that are they innocent until proven guilty or guilty until proven innocent? Now, the one I talked to you about, in fact, all the in-silico things would say that it's benign anyway, and we know that they're mostly benign. We're not doing that for synonymous variants. So I think in terms of going, often you can't do the segregation, the families are too small, the chance of being able to really sort that out in terms of a lodg score for breast cancer, which has got a high phenocopyrate, which also impacts in that, so it makes it very difficult. It's quite difficult. So I think the problem that has is people go back to them and you're telling them, if people knew that it was innocent rather than proven guilty and they were doing it on a purely exploratory fashion, I wouldn't have so much problem with it. But I think what happens is people are assuming that if the doctor is telling you this or the doctor is actually telling that it is likely to be pathogenic, that we have a problem there, and so currently we're doing more harm than good. So it's part of that balance, but I appreciate it's a difficult issue. Great, thank you, and we'll definitely have time after the panel's all done for more questions.