Dr. Emilia Modolo Pinto Answers Questions About Cancer Predisposition Genes and Childhood Cancer in LFS and Beyond.

Research articles often are difficult for the average person to understand. One of our goals at living LFS is to help make this information easier to understand so everyone can benefit from the exciting advances in science and medicine. In November, The New England Journal of Medicine published an article about childhood cancer, hereditary cancer genes and predisposition to cancer.   Dr. Emilia Modolo Pinto graciously agreed to answer a few questions to help us better understand the article and what it means for not only the LFS community, but for the public in general.

Emilia Modolo Pinto, Ph.D., is a researcher at St. Jude Children’s Research Hospital. She studies adrenal tumors in children, which are often associated with Li-Fraumeni Syndrome and TP53 mutations. In this interview, she talks about her work studying Li-Fraumeni syndrome.

Dr. Pinto, please tell us a little about yourself and how you became interested in hereditary cancers.
EMP: I finished my Ph.D. in Brazil in 2005. Since then, I have been studying tumors of the adrenal gland in children – adrenocortical tumors. Specifically, I study the molecular biology of these tumors – how they happen at the most basic level, the cell. Pediatric adrenocortical tumor is a rare disease, but there are many cases in southeast Brazil. In this area, it is strongly associated with a mutation in a gene called TP53. For families who are interested, the mutation is called R337H. When I was doing research for my Ph.D., I had the opportunity to study several families who have this mutation. For some families, I was able to study 3 or more generations. I learned that the mutation in the TP53 gene was passed down, without change, in every generation I studied. I also found that this mutant gene was the same in other families. The Brazilian families who have this TP53 mutation all have a history of many different cancers. Some families have a child with adrenocortical tumor, and other families have different tumors in all generations and in all ages. The situation in Brazil caught my attention and gave me an interest in hereditary cancer.

 

Recently, the New England Journal of Medicine published an article about germline mutations in predisposition genes in pediatric cancer. Can you tell us what germline mutations in predisposition genes are, and briefly summarize what this article was about?
EMP: Yes. The cells in eggs and sperm are called “germ cells.” What scientists call “germline mutations” are mutations in these specific cells. When a germ cell with a mutation joins with another germ cell to form an embryo, every cell in the embryo will carry the mutation. Now, some of these mutations affect genes called “predisposition genes.” If these genes have a mutation, they make a person more likely to develop cancer. So if a germ cell mutation affects 1 (one) of these predisposition genes, it can increase the chance of developing 1 (one) or more cancers. It’s important to stress that everyone responds differently to gene mutations. Even if everyone in a family has the same mutation, affecting the same predisposition gene, some family members will get cancer and some will not. In the New England Journal of Medicine article, the authors studied 1,120 children with cancer. They carefully examined the germline sequence of 565 genes reported be associated with cancer, and paid close attention to 60 predisposition genes that are known to increase cancer risk if 1 (one) copy of the gene is changed. Remember, a child gets 1 (one) copy of each gene from the mother and 1 (one) from the father. So, these particular predisposition genes are known to increase cancer risk if just 1 parent has a mutation. In this study, almost 9 percent of patients had germline mutations in 21 of those 60 genes that scientists paid close attention to.

 

People with Li-Fraumeni syndrome, or LFS, have mutations in their germline TP53 gene. In this article, researchers studied those mutations and several others. The results of the mutations and cancer types in the study seemed to be somewhat unexpected. What were the main things researchers learned from this study?
EMP: Researchers studied several predisposition genes, not just TP53. They chose which genes to study by reviewing the medical literature, what is already known. They also reviewed genetic databases. Usually, patients who have a lot of cancer in their families, or what we call a strong family history, have genetic testing. They get tested for a mutation in a cancer predisposition gene. But in this study, the researchers found that more than half of children with germline mutations in predisposition genes did not have a lot of cancer in the family – or any at all. They had what we call a negative family history of cancer, meaning cancer did not seem to run in the family. The results of this study will help researchers find more people with mutations in certain families. These people can benefit from genetic counseling, examinations, and tests to check for cancer. The study results will also affect how doctors take care of people with Li-Fraumeni syndrome. They will be able to find and keep track of these patients and families better.

 

Some mutations were “deemed to be pathogenic or probably pathogenic.” What does this mean?
EMP: There has been a lot of progress in genetics since the early 2000s, and scientists have found many mutations. Some of them are what scientists call “pathogenic” mutations. This means they lead to disease, such as cancer. Scientists have studied these mutations in animals, and they know having the mutation keeps cells from developing normally. Other mutations are what we call “probably pathogenic.” We can find a mutation that probably keeps cells from developing normally. But studies in animals have not yet shown that the mutation definitely causes disease. In other words, we do not know enough about those mutations yet. Even though the “probably pathogenic” mutations are associated with cancer, we need to learn more about how they cause it.

 

Why do you think the study group included more patients with leukemia and adrenocortical tumors than expected?
EMP:  This study was part of the St. Jude -Washington University Pediatric Cancer Genome Project. The cancers studied in that project are difficult to treat. Or scientists don’t yet understand how these cancers develop. Adrenocortical tumors and the types of leukemia in this study fall into these categories. For people who are interested in comparing studies, this study was able to analyze more cases of leukemia and adrenocortical tumors, compared the Surveillance, Epidemiology, and End Results (SEER) program.

 

The article says, “Discovery of 4 germline mutations in the TP53 and RB indicates that a fraction of the mutations in this study were de novo.” What are de novo mutations? Does this mean that some children in this study had a hereditary mutation, but did not actually inherit it from their parents?
EMP:  “De novo” mutations are mutations that are found for the first time in 1 (one) family member, but not in either of their parents. A de novo mutation can come from a mutation in an egg or sperm cell from 1 (one) parent. Or it can come from the fertilized egg itself. To learn if a mutation is inherited or “de novo” the parents of a child with the mutation should be tested, to see if they also have it. However, it’s important to know another reason that we sometimes cannot find a mutation in the parents. A condition called ”mosaicism” ,means they have the mutation in some of their cells, but not all of them. This can make a mutation difficult to find with common genetic tests.

 

I have Li-Fraumeni Syndrome and so do my children. What do the results of this study mean for us?
EMP:  Mutations in the TP53 gene are probably the most common cause of cancer in children. So there are probably many more children with LFS than we know about right now. Children and adults with germline TP53 mutations need regular examinations and tests to screen for cancer. This can help find tumors as early as possible, when they are most likely to be cured.

 

What does this study mean for the public?
EMP:  Scientists are learning more about what having a germline predisposition mutation means for childhood cancer. Knowing this type of mutation is present will help doctors care for patients more effectively. It will also help doctors care for family members of people with mutations. We know more about the risk of cancer, and knowing the mutation is there helps us decide on care and treatment for patients with mutations. Also, regular examinations and tests for patients with mutations will improve cancer care, because doctors can find and treat tumors earlier. Perhaps in the future, it will even be possible to prevent tumors from forming.

 

There are some very valuable take away points from this article. Children shouldn’t get cancer and when they do, researchers are now finding that family history isn’t always the only indication of a possible germline mutation. To serve the pediatric population better, to find better treatment and screening, genomics and genetics will play an even more important role as we go forward. The hope is that some day we will be able to prevent these mutations and the cancers they cause. We’d like to thank Dr. Pinto for sharing her time and knowledge with us.

 

The study referenced in this interview is from the St. Jude Children’s Research Hospital — Washington University Pediatric Cancer Genome Project and appeared in the November 18 edition of the New England Journal of Medicine.

 

Journal Reference:

Zhang et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. New England Journal of Medicine., Nov. 18, 2015 DOI: 10.1056/NEJMoa1508054

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