Siddhartha Mukherjee: Here is another provocative question. Some cancers such as prostate cancer are age related clearly, whereas other cancers are not. Acute lymphoblastic leukemia arises in children. Why is it that only some cancers are age related and other cancers are not age related, Dr. Schrag, Dr. Schwartzentruber, clinicians?
Doug Schwartzentruber: I don’t have a good answer for you. We do know that the immune system is differently developed at various stages in life and that may be one clue that now the host factors, as you deposit a tumor or a cancer in that patient may behave differently through ages, but I’d look to epidemiologists to give us an answer. [00:56:39.06]
Deborah Schrag: We don’t know. I mean we know that for example, for some types of leukemia as you well know folks are born with predisposing mutations and there is sort of the idea of there being a second hit or multiple additional hits and these exposures may occur at different points in the lifestyle, so at different points across the lifespan, so for example, if hormonal environment is very important. Perhaps it’s not a surprise that we don’t see prostate cancer in adolescent boys. We never see prostate cancer in adolescent boys, so that right there is telling us something, but there is more here that we don’t know. Epidemiologists try to figure this out, try to understand this. We know that Hodgkin’s disease; there is a few diseases that have two peaks, testicular cancer and Hodgkin’s disease. Both have what we call a bimodal distribution. They’ve got a peak around the teenage years and then there is another late peak in the 50s and 60s. The diseases sort of look that same at the moment under the microscope, but are they really the same? Probably not, we’re not quite there yet, but there is some tantalizing clues. [00:57:50.03]
Harold Varmus: I think there is- it’s worth thinking about one problem that most scientists have not focused on. That is, what is the cell in any organ? Every organ is made up of cells in lineages, stem cells and intermediate stage cells and the most mature, highly functional cells and we don’t know in the vast majority of cancers which cell is actually the target cell for developing a cancer. If we knew the abundance of those cell types and the number of cell divisions they go through and the likelihood they’re exposed to mutagenic events I think we begin to get a better picture. For example, one way to think about this is a disease called retinoblastoma, largely a hereditary disease that requires one additional mutation is only seen in kids up to the age of six and we know the target cell for that disease, the retinoblast disappears in the eye, so there is no target cell anymore and that is why the disease occurs early in life. You could argue that in contrast a disease like prostate cancer arises in an organ that has a certain number of stem cells throughout life and you’re just waiting for mutations to accumulate as they continue to do throughout life and the disease gets more frequent with increasing age.
Siddhartha Mukherjee: And breast cancer for instance, we know that the length of hormone exposure, estrogen exposure is critically important, so you need so many years of hormone exposure before you finally get your malignant cell.
Lewis Cantley: Yeah and I think the example I gave earlier of these rare heart cancers that appear even before birth, but then disappear, so I think those examples and probably the other examples we heard of where you get this bimodal event are probably driven early, the early event is probably driven by some hormonal environment, some growth factor hormone is peaking at that stage as you go through puberty for example and that is actually substituting for one of what would otherwise be a mutation required, so now you only need on mutation plus a high level of that hormone and that drives it at that stage. The older form is probably mutations that are replacing the need for the hormone coming up with age, so they’re less probable to take longer to appear, but ultimately result in a similar disease.