Urologic Oncology

SLIDES & TRANSCRIPTS
Saturday, December 14, 2002

Hereditary Testicular Cancer: Clinical Implications

Mark Greene, M.D.

Slide 1:

Good morning, ladies and gentlemen. It's a pleasure to be here, and a real privilege to appear before such an austere group. I hope you won't take advantage of an internist being on the podium to go get your coffee at this point. I think you will find some of the things that I have to share with you very interesting.

Slide 2:

By way of background, you have seen these kind of epidemiologic slides many times in the past, I'm sure. Testicular cancer, of course, is the most common tumor in young men. Its incidence has been rising over time, particularly in Western countries, the US and Northern Europe.

The lifetime risk in US white men is about 1 in 500, and this disease is significantly less common in men of African-American heritage. Although the number of new cases anticipated on a yearly basis is relatively small, this is a disease that has an impact that is disproportionate to its incidence, because it affects young men in the prime of their lives.

Slide 3:

There has been a fair bit of work done over the years on risk factors for this disease, and I am sure they are familiar to all of you. I will focus on microlithiasis and its relationship to testicular cancer, testicular intraepithelial neoplasia (TIN), and then the bulk of my presentation will deal with familial and genetic factors.

Slide 4:

My own view is that at present, the relationship between microlithiasis and testicular cancer is insufficiently studied, but there certainly is a large literature to suggest that there is a relationship.

On the left you can see testicular ultrasound in which there are multiple punctate calcifications. This individual was followed expectantly, and some time later developed a mass in the midst of this nest of calcifications, which proved to be a malignancy. And it's data like these that suggest to many people that there is a relationship between these two entities. We'll be looking at this in our families, but the relationship is not as clearly established as we might like it to be.

Slide 5:

The entity of testicular intraepithelial neoplasia(TIN), is I think less well appreciated at least in the states as a precursor lesion for testicular germ cell tumors. Most of the work on this entity has been done in Europe, where TIN cells are felt to represent malignant gonadocytes that arise in utero, and are thought to be present in nearly all individuals who are destined to develop testicular germ cell tumors later in life.

Interestingly, the prevalence of this lesion in the contralateral testis of men who have been treated for unilateral testicular cancer is about 5-6 percent, which is a rate that corresponds to the lifetime risk of developing an invasive contralateral testicular cancer in men with an initial primary.

Slide 6:

This is probably the best study that has looked at this entity. A European series of almost 2,000 patients with unilateral testicular germ cell tumors, who underwent biopsy of the contralateral testicle in search of this entity. Intraepithelial neoplasia was detected in about 5 percent of the patients who were biopsied.

In Europe it has become standard of care to treat these patients with low dose radiation to the involved testicle. The dose of radiation is low enough that fertility is preserved. And in those instances where biopsies following treatment have been done, the precursor lesion has resolved.

In their series there were only three patients who had biopsies that were negative for TIN, who subsequently developed germ cell tumors during prospective follow-up. And they also noted that those individuals in their series who had testicular atrophy, were much more likely to have intraepithelial neoplasia than those without. And as you are aware, testicular atrophy is one of the known testicular cancer risk factors.

Slide 7:

The risk of TIN progressing to invasive disease is estimated to be about 50 percent in the European experience, but they argue since no one has ever documented spontaneous regression of this lesion, it's their view that virtually all cases of untreated disease will progress to invasive cancer if left untreated.

Slide 8:

Turning now to familial clusters of testicular cancer, those of you who see these patients I'm sure are aware that multiple case families are exceedingly uncommon. The pattern of affection within families is very different from that seen in the other hereditary adult cancer susceptibility disorders that we have become more comfortable with.

Families for example, with many affected individuals over multiple generations, are quite rare. And in fact, most of the reported cases of high risk families involve only two cases per family.

In formal genetic analyses that have been done to evaluate possible genetic mechanisms underlying this risk, an autosomal recessive model fits the data best, with the genetic characteristics as shown here. I think the most important feature is that the estimate is that about 1 in 1,000 men would be homozygous for this putative recessive gene, which makes it a rare disorder indeed.

Slide 9:

Just to remind you of what a family tree looks like in a recessive condition, because it strikes the eye in a totally different way than autosomal dominant conditions do. In this diagram, the vertical bar indicates people who are carriers of one copy of the mutant allele, and the orange symbols indicate those individuals who have two copies of the mutant allele.

And the critical features of autosomal recessive inheritance are that two germ line mutations, one inherited from each parent, are required to develop disease. Consequently, the abnormal allele may be transmitted equally by both males and by females. And finally, men and women are equally likely to be affected, just by virtue of the 50-50 ability to inherit a mutant allele from each of their parents.

Slide 10:

Now, in the epidemiologic literature the risk of a family history for testicular cancer has been evaluated, and in general, sons of fathers with testicular cancer have a significantly increased risk in the range of 4-6 fold for testicular cancer. Brothers of affected siblings have a higher risk, 8-10 fold. And this is compatible with the autosomal recessive, or even an X-linked recessive mode of inheritance. And twin brothers of course have an even higher risk, nearly 40 times that expected.

In various case series, only about 2 percent of men with testicular cancer report a positive family history. However, most of these publications have been based on retrospective chart reviews in which a family history was not systematically sought.

And my hunch is that when we take a more detailed family history, that this proportion is likely to rise significantly. And there is an ongoing case control study of testicular cancer taking place within our division that will give us a better estimate of this figure over the next couple of years.

Slide 11:

There is an organization called the International Testicular Cancer Linkage Consortium, which is a multi-institution scientific collaboration that has taken the lead in trying to identify familial testicular cancer susceptibility genes. They have assembled a series of about 300 multiple case families, which are now being used for gene mapping and cloning studies. In the evaluation of the first set of families that were seen by this group, it was recognized simply by inspecting the pedigrees of these families that about a third of the families had a pattern of inheritance that was compatible with an X-linked cancer susceptibility disorder.

Slide 12:

Linkage analysis that was done in this initial set of families identified a candidate locus on the X chromosome band q27, very close to the site of the fragile X gene. The LOD score, the statistical measure of linkage was 2 overall. In general, a LOD score of 3 is required for linkage to be considered proven. But if the analysis was restricted to that subset of families in which there was at least one family member with bilateral testicular cancer, the LOD score rose to 4.7, which is a highly significant result.

In this analysis, this particular locus appeared to account for most of the family clusters in which there was an affected family member that had bilateral testicular cancer. And in spite of an intensive search, at least to date no candidate gene has been identified in this region. This is an area of active investigation by the linkage consortium.

Slide 13:

And this is to illustrate for you what X-linked inheritance looks like. This is even harder to kind of think of as hereditary when you map a family like this out. And the symbols here, the colored circle in the center indicates that the person is a carrier of a mutant allele on the X chromosome. The orange symbols indicate those who are affected. If you look at the pedigree, you have a proband and his uncle who are affected. They don't appear to be very close relatives. Upon first glance you might think that the odds of this being a genetic disorder are small.

But given the nature of X-linked inheritance in which the mutant gene is located on the X chromosome, this means that for a woman to be affected, they have to have two abnormal X chromosomes, the likelihood of which is exceedingly small. Since men carry only one X chromosome, they are therefore much more likely to express the manifestations of an X-linked susceptibility allele.

The other point I would make is that a father to son transmission cannot, by definition, occur in an X-linked disorder, because the mutant allele has to be passed on through the mother. Men get their X chromosomes from their mother. There's no way to get it from your father. So if you see a family where there is father to son transmission of so-called disease, it cannot be compatible with X-linked inheritance.

Slide 14:

In the linkage consortium data set, many of the families that are not linked to Xq27 have a disease pattern that in fact is not consistent with X-linked inheritance, primarily because there is evidence of both affected fathers and sons in those families. And that suggests that there likely other susceptibility genes on the autosomes that have not yet been identified. And in their initial linkage analysis, a number of candidate regions have been identified that are under active investigation at the present time.

Slide 15:

So when I came to NCI about three years ago to develop a clinically-oriented genetics program, I was of the opinion that testicular cancer was ripe for further investigation. And so we have developed a program of studies that I would like to briefly tell you about this morning.

We begin by trying to ascertain new multiple case testicular families. And then we bring as many of those families as we can to the NIH clinical center for a multidisciplinary study. And I'll give you the details of that in just a moment.

Part of our goal is to define the clinical phenotype of familial testicular cancer. And one of the kind of assuming things about this modern genomic era is that people seem to have focused exclusively on the DNA that families like this can donate, and pay relatively little attention to what these people look like clinically.

Our intention is to bring as many of these families to the clinical center for detailed clinical assessment as we can. And at the same time of course, we will collect their DNA and contribute that DNA to the consortium for the ongoing mapping and cloning efforts.

In addition, we have established a formal collaboration with the International Linkage Consortium, and they of course are continuing their efforts in gene mapping and cloning. There are two sub-studies that we are doing in collaboration with them. One is a central pathology review of the familial testicular tumors, and the second is an attempt to analyze the risk of cancers other than germ cell tumors in these families, to see if there are in fact non-germ cell malignancies that are part of this disorder.

Slide 16:

The objectives in our clinical study are: to find new families and to characterize the clinical features of this disease by analyzing medical history, reproductive history, and various testicular cancer risk factors.

We will search for genito-urinary anomalies, both clinically and radiographically, that may be etiologically related to this disorder. We will assess fertility status in both males and females, because of the relationship between infertility and testicular cancer risk.

We also intend to seek evidence, both clinically, radiographically and molecularly, of clinically occult invasive testicular tumors, and intraepithelial neoplasia in male family members who are at increased genetic risk.

In our initial set of patients, we will look very carefully on clinical evaluation for subtle dysmorphic features in these families. If this is a disease that has an intrauterine origin, as is hypothesized, there may in fact be subtle malformations associated with this syndrome that would be identifiable when viewed by someone who knows really what they are looking for.

And we are also interesting in evaluating women for a potential carrier phenotype in these X-linked families. There is a growing literature to suggest that one copy of a mutant allele may not be inconsequential as has been historically thought. And so we have an opportunity in this study to look at what happens to the women who are carriers of this allele as well.

Slide 17:

We will also review psychosocial and behavioral issues in these families, developing a specimen resource for laboratory studies, and contributing to the linkage consortium.

Slide 18:

The eligibility criteria for our study are as follows: two or more family members with disease; bilateral disease; someone affected who is a member of a set of identical twins. People must be 12 years old to participate, and both affected and unaffected family members will be screened.

Slide 19:

Accrual will be from multiple areas. Hopefully, many of you have received our mailing announcing the opening of this study.

Slide 20:

Here is our website, for those of you who are interested in more information. And in the handout, the URL for this site is listed.

Slide 21:

Slide 22:

Marston Linehan, MacClellan Walter and their colleagues from NCI urology are involved in this project as well.

Slide 23:

In conclusion, we have launched what I think to be a fairly comprehensive, multidisciplinary program of studies related to familial testicular cancer, which incorporates laboratory and epidemiologic components. The project includes intramural investigators from my program, my division, from the Center for Cancer Research, and extramural colleagues, both here and abroad.

Slide 24:

We need referrals of these rare families if we are going to be able to move this field forward. The clinician in my group who has the lead on the family studies is Joan Kramer. You can call her directly. You can call me directly if you want. And we also have an 800 number where you can call our familial referral line.

So with that, I thank you for your attention, and look forward to working with you, and reporting progress on this study in the future.