I’m going to be talking about the inherited genetics or inherited susceptibility to testicular cancer. So testicular cancer is actually probably, if not the, one of the highest heritable cancers so that the risk to brothers of patients with testicular cancer is about eight- to ten-fold and the calculated risk to fathers is about four-fold. So many studies were done to try to understand what the genetic variation was or inherited genetic variation that predisposed to testicular cancer. Looking for single genes such as BRCA1 or 2 or other high penetrant genes was very unsuccessful. It wasn’t until the era of genome-wide association studies that people were able to identify variants associated with testicular cancer. In fact, the genome-wide association studies in testicular cancer have been the most successful in all cancer types and it’s considered the clinical poster child for genome-wide association studies in cancer. So we’ve identified over 25 variants in the genome which are associated with an increased risk of testicular cancer. The first one which was identified in 2009 was a variant that’s associated within the KIT ligand. So the KIT ligand actually is the protein that guides the migration of germ cells during development so part of it, the truncated form, actually is in the genital ridges and acts as a chemo-attractant and a full length form guides the germ cells down to the genital ridges. So mutations in that which allow the germ cells to go to other places, not the genital ridges, increases the risk of testicular cancer with a very high per-allele relative risk. Essentially everybody with testicular cancer carries the risk allele.

So the other thing that’s very interesting about testicular cancer is it’s essentially a disease of white men and the allele that was identified is much, much more frequent in whites than it is in blacks, it’s almost non-existent or very low frequency in blacks. So that initial identification of that variant allowed us to understand that variants that have to do with germ cell development and germ cell migration are associated with testicular cancer and that differences in allele frequency also probably account for racial difference in the observed epidemiology.

Since that time about 20-25 loci have been identified so there are several things that are particularly notable about them. One is that they’re at much higher risk than for other genome-wide association studies. So for example breast cancer, a common cancer people think of as being familial, there’s only one or two loci that have odds ratios over 1.5 whereas for testicular cancer there are about six loci with odds ratios over 1.5 and then the rest of them have an odds ratio of over 1.2 whereas for breast cancer in fact they only have another one or two loci with an odds ratio over 1.2 and all of them have very low risk. So this is a very inherited disease with a lot of polygenic risk factors.

The other thing is that the biological pathways have become really self-evident out of these studies and so it’s very clear that if you perturb in any way germ cell development or germ cell maturation that you get testicular cancer. It’s not associated with development of other cancers, we’re not really finding loci that have been identified for other cancers except very occasionally in some that are associated with DNA damage and DNA damage response. The other thing that looks to be unique to testicular cancer, interestingly enough, is that there are a lot of loci that encode proteins that have to do with chromosomal segregation. So when you go through mitosis or division of the chromosome you have proteins that guide them and surprisingly that had not been identified as susceptibility loci for other cancers but is for testicular cancer. So we really have very clear biological pathways that have been implicated in testicular cancer.

So what we know is a lot more about the disease and the biology of the disease from doing the inherited studies and what does the clinician need to know? Unfortunately there’s not a single risk factor, however we know it’s highly heritable that relatives are at increased risk. There are some other associated risk factors such as cryptorchidism or when the testes don’t descend and those people in the future, we hope, will be screened for the increased risk variants and those people go on and have screening usually through scrotal ultrasound for testicular cancer because those are going to be the people at highest risk because it looks like the risk factors for cryptorchidism are distinct from those risk factors for testicular cancer.

Should we be encouraging family members of those diagnosed to get checked also?

Yes, I do actually think that it’s important for them to realise. Now the point that’s important to know is that even when we talk about eight- to ten-fold increased risk the absolute risk is still very low, it’s still 2%. But those people are clearly at much higher risk and so they should be aware if they feel a lump; not that all men shouldn’t be aware that if they feel a lump they need to get it checked out, but those men in particular should be ones who go very quickly and early to have things examined.

Does this call for new subtypes and classification?

So that’s actually a really interesting question. It turns out in testicular cancer there are two major subtypes, the seminoma subtype and the non-seminoma subtype. So the seminoma subtype actually develops from the spermatocytic lineage and the non-seminoma subtype develops from an embryonal lineage. It looks like, though, that both subtypes come from what we call the primordial germ cell, so very early on in development. From that primordial germ cell the risk factors are no different because they’re influencing that very early primordial germ cell and so far we haven’t identified loci that appear to be associated with one subtype or the other, unlike for breast cancer where there are loci that are associated with ER positive versus ER negative breast cancer. So it actually turns out that that’s not the case. Even we’ve actually studied… I’ll talk about tomorrow, which is the largest case study, even when we stratify by histology we don’t find much of a difference.

Is there the potential to tailor treatments?

So that’s an interesting question. I think that one of the things that hasn’t been done that I think is really… we’re talking about susceptibility, loci or inherited loci, is how do we link those with somatic genetic changes and how do we link that with what’s happening. So that’s one of the things we’ve been talking about as part of the GCGA project, which is part of testicular cancer TCGA, is there a way that we can link and see what’s happening? The inherited genome, does that predispose to certain things that happen in the somatic genome or the genome of the cancer and how can we link those things together? So those studies are still ongoing, it may be possible that we do it. Now it’s important to note that the KIT ligand, which is the variant that has the highest risk of testicular cancer, its ligand KIT is actually the most commonly mutated somatic mutation in testicular cancer. So there’s clearly an interplay between what’s happening on the inherited side and what’s happening on the somatic side. So hopefully eventually we’ll be able to do that.

In an ideal world should everyone get their genome sequenced?

That’s a totally different question. No, is actually the answer to that question. The reason is, and I’m a clinical geneticist so you’re really asking something that I’ve actually thought about, is that the problem is that there is so much variation in the genome that it’s so difficult to interpret what you find in the absence of a disease, particularly for healthy individuals that you create a lot of anxiety for both patients and physicians. And actually particularly for physicians, interestingly enough, where you don’t really have anything that you have to offer. So as a geneticist and as a practising clinical geneticist, I believe that genetics and genetic testing is all about medical management. So why do we do things? We do them because we are going to change our medical management or we need to understand the etiology of something or people are at reproductive risk and we’re changing how their reproductive decisions are. I think that’s good when you have a disease and you’re looking for an etiology or you’re looking for a cause or you’re looking for something that’s going to change someone’s medical management. I think it’s very difficult to know how to interpret all that data in the absence of disease.

The other thing that I think that we’re running into, and this is actually something you think about, is that we know that any time we do a test there’s a prior predictive value of that test. The problem is that what you do when you sequence lots of individuals is the prior predictive value of what you’re finding is incredibly low, it’s much more higher likelihood that you’re finding a variant that you don’t know what it means than you actually find something pathogenic. So when you weigh the risk-benefit I personally don’t think we should be at this point sequencing everybody’s genome and giving them the data back. Maybe for research purposes yes but I think for clinical purposes we’re not there yet.