How did you get into the study of the genetics of human tumors?

I’m a human geneticist by training. Within that discipline I specialize in what’s called cytogenetics. Besides my research, I run a clinical diagnostic lab that does chromosome testing. We look for chromosomal abnormalities present in prenatal samples for prenatal diagnosis. We also do a lot of testing nowadays on bone marrows for leukemias and lymphomas, and also solid tumors. That’s how I got into uterine fibroid research; I was initiating a clinical service in solid tumors in a diagnostic lab in the late 1980s.

   Has the focus of your research changed over that time?

In some ways it hasn’t. I’ve always been trying to understand the biology of these tumors using genetic approaches. As a cytogeneticist, I am very interested in the chromosome rearrangements that occur in these tumors and the result of those rearrangements to illuminate genes that would be participating in the aberrant cell growth.

Well, one of the ones we have worked on most is in the area of chromosome 12, and it typically comes with a translocation of chromosome 14. By looking at these rearrangements, we know the region of the genome to focus on to look at genes that may be important in these tumors.

That’s a whole different question. The cytogenetic events we see are somatic events; they occur in the cells of the tumor, but if you look at normal cells of individuals, you wouldn’t expect to find that rearrangement.

Cytogenetic rearrangements are very common, but that particular one is pretty specific to uterine fibroids. It’s very characteristic of these fibroid tumors. If you saw this rearrangement and somebody asked you what tumor it came from, you’d say it must be a fibroid.

Well, first of all I know this is the most cited, but I’m not sure necessarily that it’s more of a landmark than some of others. That said, we first found the gene in the 12-14 translocation, when we looked at the genome sequence. We also found a highly related family member and that gene happened to be on chromosome 6, and we knew that we had tumors with rearrangements of that specific place on chromosome 6. So this paper in 1997 is actually confirming that the gene on chromosome 6, a family member of the gene on chromosome 12, is also involved in uterine fibroids, although we don’t see it as frequently as we do this other rearrangement.

I guess if you’re going to start citing who did the work on chromosome 12, and who did the work on 6, two groups did the work on 12, but you might not actually find our paper. In fact, you don’t even have my paper on 12 listed. We actually first found the gene on 12 involved in lipomas, and basically we speculated that that’s the same gene as in fibroids. Then another paper came out right after ours saying this is the gene in fibroids. That was in Nature Genetics and the first author was Eric Schoenmaker. Then we published our paper saying that the chromosome 6 gene was also involved in fibroids. So my guess on the citations is that when people look into the fibroid literature for what to cite, they pick up this other paper on 12 and our paper on 6.

From the lay perspective, in some ways we do all the work to get to the sequence. Once we have the sequence, then what does that tell us? We have to find the genes in the sequence. Then we find the genes, and it brings up this question: what does the gene do? In biology, in a way, we tend to work backwards: we find the gene and then try to figure out what it does. So the gene on 12 is called HMGA2, and the one on 6 is HMGA1 (HMG stands for high mobility group). These are a family of proteins that bind DNA and bend it, and they bend it so that other factors, other proteins, can get access to the DNA to transcribe it. They’re called accessory transcription factors. They don’t really cause transcription themselves but they facilitate it. And that’s what we’ve been learning.

In that paper the punch line is that when you karyotype the tumor, sometimes you find more than one population of cells, and this is particularly common in the subset of fibroids which have a deletion on chromosome 7. But we almost never see that without also seeing it in normal cells in culture. What you can say is that because the tumor you got wasn’t all tumor, you got some normal tissue along with tumor. On the other hand, it’s not so difficult to really be sure that you have only tumor in these cases, because the tumors can comprise very distinct nodules. So it’s not that difficult to dissect them from normal tissue. Then the question is can you prove that the cells that are in that tumor all came from the same origin, or is it what we call polyclonal? Is it monoclonal or polyclonal? You can use these polymorphisms in the genome on the X chromosome to ask this question. Can you find out whether all the cells have the same parental X chromosome inactivated or not? You can use that as marker to see if all the cells in the tumor are expressing the same X chromosome. You wouldn’t expect that to happen by chance. So we analyzed the polymorphisms and found that even in the tumors that have two different karyotypes, only one X chromosome was being expressed. That implies that the chromosomal abnormalities occurred after the tumor was initiated—it was part of the evolution of the tumor.

Never discount the importance of luck in science. Although I don’t know if you can really refer to luck in anything having to do with the Human Genome Project. Still, when we were first looking for the gene on chromosome 12, we were obtaining clones for doing mapping from a group at the Albert Einstein College of Medicine that was making a map of chromosome 12. They were trying to line up all the DNA fragments. So one day one of my graduate students came in and said she had found a clone that spanned the breakpoint of this translocation. Normally it should only be on 12. Now part of it was on 12 and part was on 14. So it would be reasonable to assume that the gene involved in this is included in that piece of DNA. So we called this group at Einstein and told them of this finding, and it turned out they were working with someone else who had mapped a gene into that same DNA. So they said that I’d have to talk to this other investigator—those results were unpublished—and see if he would like to pursue it together, which worked out. And it turns out that was the gene we were looking for.

The biggest challenge is simple: doing it fast enough to really impact patient care. I think that’s true about all of genetics. I think, in the aggregate in my lifetime, we have learned a tremendous amount, but we’re still low in terms of being able to offer a lot to patients. I guess the dream that I hold out for is that by understanding what these proteins do, we can figure out how to lower the expression of these genes so that they don’t end up telling cells to grow when they’re not supposed to be growing. So what we would hope for is a gene therapy or medical therapy that would silence these genes or lower the expression.

We really are beginning to know the genes involved. That’s the bottom line, and what pathways they work in. We’re beginning to understand the biology.

We are currently involved in looking in a genome-wide fashion for genes that cause the predisposition to develop these uterine fibroids. The way we do that is by collecting sister pairs who have fibroids. We need about 500 sister pairs and their relatives, and then we can try to see if we can find regions of their genomes that are involved in a biased way. We have now collected around 310 sibling pairs, so we’re busy trying to recruit women for this study. We’ve been running advertisements. I’m even hoping that just by talking to you maybe some woman will read this and decide, with her sister, to join our study. We send a questionnaire so we can get their health history. We are interested also in knowing whether there might be some associated environmental factor that might be related—diet, for example, or smoking, or the use of oral contraceptive pills, things like that. More than anything we hope to identify the major gene effects, the ones that would be present in the largest number of individuals. There is a health disparity issue here, too. These fibroids affect African American women more often, so we would very much like to find what gene is involved in that population. We’re trying to target our recruitment to that population, as well. I’m still hoping someday to get a spot on Oprah Winfrey’s show. A half-dozen years ago Michael Milliken went on Larry King Live to talk about prostate research and it made an enormous difference. I figure if we could get on Oprah, she could empower women to participate.