Earlier, in mid December, a study was published reporting that a cancer in children is very different from cancers in adults. Specifically, the study suggests that there are far fewer mutations present in some childhood cancerous tumors than in tumors of adult cancers. This could have significant implications for not only how we approach and treat childhood cancers, but how we treat combat cancers in general.
The study, which was published in the journal Science, was a large collaborative effort involving 20 different medical institutes, cancer centers, and universities in the U.S. that looked at the genetics of a very aggressive brain cancer found primarily in children called medulloblastoma. Although medulloblastoma tumors originate in a certain area of the brain, the cancer can spread through the spinal fluid to other parts of the central nervous system (which includes the brain and spinal cord). Every year, about 1 in 200,000 children under the age of 15 are diagnosed with having medulloblastoma, and although therapies to treat them have improved, still many cannot be cured and often there are severe side effects from the therapies. It’s a devastating cancer. Medulloblastoma is very rare in people over 40, which most likely has to do with how medulloblastoma comes to be.
Although its identity has been hotly debated in recent years, it’s now thought that medulloblastoma is created from cells that were primitive neural stem cells. Such neural stem cells are normally present during fetal development, but in patients with medulloblastoma, these stem cells have mutations in their DNA that led to the formation of a highly malignant tumor.
The study To test whether, and how, medulloblastoma in children is different from adult cancers, the researchers looked at the DNA from 22 different medulloblastoma samples from children as well as DNA from several different adult cancers (including pancreatic, glioblastoma, colorectal, and breast cancer tumors). The DNA sequences of all known genes were analyzed both in tumors and in normal, noncancerous tissues taken from the same patients. In this way, the scientists could determine which genes were different, or mutated, in the tumors compared to healthy tissue. This is commonly done when studying cancer, and identifying which genes are mutated helps us better understand what causes cancer.
Far fewer mutations in a childhood cancer than adult cancers Interestingly, the scientists found that the medulloblastoma tumors in children had about five to 10 times fewer mutated genes than several different adult tumors studied (which were not medulloblastomas). However, while the childhood tumors had many fewer mutations, over one third were mutations known to disrupt gene function, which is a much higher percentage than in the adult tumors analyzed. This may simply be because the adult cancers are in older tissues, and these tissues have had a longer opportunity to gain random mutations over time, but it’s difficult to tell. Either way, this shows that childhood cancer is very different from adult cancers.
The likely suspects How can we use our knowledge of these differences between childhood and adult cancers to help us better combat cancer? To answer this question, it’s important to look at exactly what the researchers found, which comes down to some very specific genes that probably play central roles in causing cancer.
Some of the genes commonly mutated in the medulloblastoma tumors belong to two different groups of well-studied genes, the Hedgehog and Wnt gene groups. (Many genes have somewhat whimsical names, mostly due to early studies in fruit flies; the Hedgehog genes, for example, don’t have anything to do with the hedgehog animal.) These groups of genes are thought to primarily function during embryonic development and during some cancers. Specifically, the mutation of some Hedgehog and Wnt genes has previously been shown to correlate with the occurrence of different cancers, including medulloblastoma.
This recent study not only confirmed previous studies linking Hedgehog and Wnt genes to medulloblastoma, but the researchers also discovered that other genes, including ones not previously suspected, may also be involved in causing medulloblastoma. These newly suspected genes belong to the histone-lysine N-methyltransferase gene family, whose members actually control whether many other genes are active or not. Consequently, by having mutations in these identified genes (which are specifically the histone-lysine N-methyltransferase genes MLL2 and MLL3), the tumors have changed the function of many other genes, causing a kind of snowball effect.
The researchers found that MLL2 or MLL3 were mutated and consequently no longer active in 16 percent of the medulloblastoma tumors they looked at. This suggests that MLL2 and MLL3 normally play important roles in preventing the occurrence of medulloblastoma—that they are what are called “tumor suppressor genes”. Additionally, it’s known that these genes are also very important during normal brain development, which again emphasizes how this childhood cancer is different from adult cancers; the childhood cancer is almost certainly the result of something going wrong during development.
Contributing to how we view cancer While the most significant finding in this study was how many fewer mutations are present in a primarily childhood cancer, medulloblastoma, compared to adult cancers, understanding the specific genes revealed to be key to causing medulloblastoma will not only change how we view and treat childhood cancer, but will also help us better understand which genes are key players in causing cancer in general. It’s becoming clearer that childhood cancer, as shown here with medulloblastoma, is due to problems that manifest during fetal development.
Additionally, the family of genes that MLL2 and MLL3 belong to has already been suspected of being involved in the occurrence of many other types of cancer, and this most recent finding with medulloblastoma warrants further investigation of this gene family and its connections to cancer.
Lastly, because this childhood cancer has many fewer mutated genes than adult cancers, it gives researchers a few genes to really focus on; the genes mutated in medulloblastomas may be the few, most essential genes responsible for this kind of cancer and most likely other cancers. Applying these findings to other cancers may be difficult. In this study, childhood medulloblastomas were not compared to adult medulloblastomas (which are very rare, but may reveal additional differences), and clearly this study has shown that not all cancers are alike.
Fighting cancer with gene therapy To date, over 80 cancers have had all of their known genes analyzed for apparent mutations. As we better understand which genes are most important for causing, and preventing, cancer, researchers can not only develop better methods for identifying the type of cancer a patient has, but can also develop better therapies to target these specific genes. For example, in medulloblastoma, thanks to this recent study, the development of drugs that target the genes MLL2 and MLL3 is a very appealing prospect, but a better understanding of these genes (and improvements in gene therapies in general) is needed before such therapies can become a reality.
For more on medulloblastoma and recent comparisons of this childhood cancer to adult cancers, see the original article published in the journal Science in December 2010, read coverage of this article by The Scientist, or see Wikipedia’s article “Medulloblastoma.”
Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at firstname.lastname@example.org.