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PPB Genetic Study Results (updated October 2011)

We wanted to update our families, collaborators and generous donors on our progress over the past two years. We are very thankful to all of the families and individuals contributing their time to help us learn more about PPB. If you haven't had time to join the study yet, please do so, We really need your help. We also want to introduce you to our outstanding collaborators who are sharing their time and expertise to work on PPB. Finally, we want to thank our generous benefactors whose support is critical in moving forward.

So here's a quick update on what is going on in our team's PPB research.

1. Mutations in a gene called DICER1 are the major predisposing factor in the risk for developing PPB or related conditions.

2. Most people who have a mutation in one copy of his/her DICER1 gene inherited this mutation from a parent who inherited it from a parent, who inherited if from one of their parents, and so on.

3. Most people having a mutation in one copy of his/her DICER1 gene do not develop PPB or other cancers. Why some people will get PPB and others will not is still unknown. The NCI study will help us better determine the exact risks of developing PPB and will also help us learn about other conditions that may be related to DICER1 mutations. The more we learn about DICER1 mutations and the health of individuals that carry them, the better guidance we can provide with regard to screening, prevention and encouragement of healthy behaviors. This aspect of the study is funded by a Bench-to-Bedside grant from the Cancer Genetics and Epidemiology Branch of the National Cancer Institute.

4. Parents who carry a mutation in one of their DICER1 genes have a 50% chance of passing it to a child. Parents have no control of which DICER1 gene is passed along to their children. Remember that the vast majority of individuals born with a DICER1 mutation will be completely normal and will not develop PPB. Knowing the DICER1 status of an infant will help guide appropriate screening tests so that if the lungs show early signs of PPB (i.e. lung cysts), curative treatment can be initiated. See our special section on DICER1 testing below for more details.

5. About 30% of kids with PPB do not appear to have mutations in the DICER1 gene. Because knowing if there is a predisposition in the family is imiportant for current young family members, future siblings and future progeny, we are working very hard to identify if these kids have mutations in a region of the DICER1 gene that we aren't currently looking at or have mutations in a gene or genes other than DICER1. It is also possible that the mutation leading to the cancer developed in the lung tissue itself, meaning that the risk to other family members or future children is essentially zero. We have received a $100,000 grant from Hyundai Hope on Wheels to begin to address this challenge.

6. One of the more difficult challenges in the research of PPB and related tumors is that the tumors are so rare, there is not much tumor tissue available to study the genes and proteins that are altered. We are very much in need of fresh and frozen tumor and normal tissue so that we can continue learning about what makes PPB grow. If you or an affected famly member are preparing for surgery, please contact us so that we can work with your surgeon and pathologist to send tumor samples for special studies. We are currently using a number of novel technologies to try and dissect the cell signaling patterns between the normal tissues and tumor cells in PPB. By identifying these signal pathways, we think we can design new treatments directed at these pathways. This work has been helped tremendously by a 5-year R01 grant and more recently a very generous $51,000 donation from the Remington Arms Company (Take Aim at PPB!). Another exciting development is a new collaboration with Matthew Myerson, Trevor Pugh, Carlos Rodriguez-Galindo and Charles Roberts at the Broad Institute. The work will focus on whole genome sequencing of 20 pairs of PPB tumor and normal tissue and is funded by a large grant from Carlos Slim-Slim Initiative for Genomic Medicine.

7. In addition to work on PPB itself, our IPPBR collaborator and pediatric ovarian tumor expert, Kris Ann Schultz, is working very hard on establishing a new Registry for Ovarian Stromal Tumors. Another understudied tumor that is part of the PPB syndrome, KrisAnn hopes to develop the resources to make great strides in understanding the biology of these tumors on the way to making treatments better and safer. Kris Ann is based at Children's Hospitals and Clinics of Minnesota where she has received $100,000 grant from St. Baldrick's Foundation and a $50,000 from Hyundai Hope on Wheels to support this important work.

8. Turning to more basic science, we have established collaborative relationships with outstanding lung biologists at Cincinnati Children's Hospital (Kathryn Wikenheiser-Brokamp) and at Washington University in St. Louis (David Ornitz). With their unique skills and experience, we are developing animal models of PPB through which we hope to learn what makes PPB grow and alternatively, what makes it stop growing. This work is currently being funded with $200,000 from St. Baldrick's Foundation, a new 4-year R01 grant from the NHLBI, and we hope to supplement this soon with a second R01 grant. Wish us luck. Look for more details to be coming out of these fantastic researchers.

 

DICER1 TESTING

In response to the many requests of the PPB Families, the Department of Pathology at Children's National Medical Center has developed a clinical assay for DICER1 mutation testing. Families wishing to know if they/their child carries a DICER1 mutation testing now have an avenue by which to obtain their individual results.

I know that many of you are really anxious to know the results for your child but because this is a test on the genetic sequence which has implications not only for the individual but also for related individuals, we strongly recommend that individuals seek advice from a genetic counselor. Your genetics counselor will explain how the test works, the limitations of the test and what each of the potential results might mean and how they might positively or negatively affect the family.

How do I find a genetics counselor?

If you do not have a local genetics counselor who can meet with you in person, either Dr. Hill (dashill@cnmc.org) or Dr. Messinger (yoav.messinger@childrensmn.org) can help you find a genetics counselor who is familiar with DICER1 mutation testing.

How does the test get ordered?

Once you have decided to have your child and/or yourself and/or family tested, the test can be ordered by your physician and/or genetics counselor.

1. Please review and sign the DICER1 testing consent form(s) and give to your physician/counselor.

2. Your physician or counselor can then fill out a DICER1 test requisition form for each individual who desires testing. Your physician/counselor should include the important medical and family history and a pedigree along with the form.

3. Your laboratory will draw 5-10 ml. of blood in a yellow top or purple top tube for each individual being tested.

4. Your laboratory will ship the specimen to Children's National:

Pathology Resequencing Laboratory

Attn: D. Ashley Hill, M.D.

Children’s National Medical Center

Department of Pathology, Rm 1620

111 Michigan Ave. NW

Washington, DC  20010  U.S.A.

(202) 476-2051 phone

(202) 476-4030 fax

 

How long does the testing take?

Testing can now be completed in 2-4 weeks from receipt. Results from the laboratory can only be given to the ordering physician/genetics counselor. Once results are available, the physician/genetics counselor will set up a meeting for disclosure to the family. The laboratory cannot release results directly to families.

For more information about the testing see:

DICER1 Mutation Testing Information Sheet

For more information about the research leading to this testing see:

DICER1 RESEARCH and PPB

 

 

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Washington University Barnes Jewish Hospital Siteman Cancer Center
Children's Hospital

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