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Gene to Age-Related Neuroblastoma Risk

St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project and Memorial Sloan-Kettering Cancer Center discover first gene alteration associated with patient age and neuroblastoma outcome

 

MEMPHIS, Tenn., March 13, 2012 /PRNewswire/ — Researchers have identified the first gene mutation associated with a chronic and often fatal form of neuroblastoma that typically strikes adolescents and young adults. The finding provides the first clue about the genetic basis of the long-recognized but poorly understood link between treatment outcome and age at diagnosis.

To view the multimedia assets associated with this release, please click: http://www.multivu.com/mnr/52992-st-jude-pediatric-cancer-genome-project-neuroblastoma-research

The study involved 104 infants, children and young adults with advanced neuroblastoma, a cancer of the sympathetic nervous system. Investigators discovered the ATRX gene was mutated only in patients age 5 and older. The alterations occurred most often in patients age 12 and older. These older patients were also more likely than their younger counterparts to have a chronic form of neuroblastoma and die years after their disease is diagnosed.

The findings suggest that ATRX mutations might represent a new subtype of neuroblastoma that is more common in older children and young adults. The work is from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP). The study appears in theMarch 14 edition of the Journal of the American Medical Association.

If validated, the results may change the way doctors think about this cancer, said co-author Richard Wilson, Ph.D., director of The Genome Institute atWashington University School of Medicine in St. Louis. “This suggests we may need to think about different treatment strategies for patients depending on whether or not they have the ATRX mutation,” he said.

Neuroblastoma accounts for 7 to 10 percent of all childhood cancers and about 15 percent of pediatric cancer deaths. In about 50 percent of patients, the disease has already spread when the cancer is discovered.

For patients whose disease has spread, age has long been a powerful but perplexing predictor of treatment outcome. Currently 88 percent of patients age 18 months and younger become long-term survivors, compared to 49 percent of those ages 18 months through 11 years and only 10 percent of patients age 12 and older.

“Until now there was no understanding of the basis of this age-related risk, and no treatment has had an impact on the outcome,” said Michael Dyer, Ph.D., a member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career Scientist. He is the study’s corresponding author. “The mutation we found is associated with patients in the older age group, but it also identifies for the first time a subset of younger patients who turned out to have an indolent form of neuroblastoma.”

Researchers must now determine whether tumors with ATRX mutations behave the same way in both children and young adults, following a similarly indolent but often deadly course, said Nai-Kong Cheung, M.D., Ph.D., first author and head of the Neuroblastoma Program at New York’s Memorial Sloan-Kettering Cancer Center.

St. Jude investigators have begun screening the hospital’s library of federally approved drugs looking for evidence of activity against neuroblastoma cells with the ATRX mutation. Availability of more targeted therapies would likely spur efforts for early identification of patients with the ATRX mutation who have a chronic form of neuroblastoma and are unlikely to benefit from current therapies.

The ATRX mutation is the latest discovery from the PCGP. The three-year project aims to sequence the complete matched normal and cancer genomes of 600 patients with some of the most poorly understood and aggressive childhood cancers. Investigators believe the findings will lay the foundation for a new generation of clinical tools.

This study involved whole-genome sequencing of the complete normal and cancer genomes of 40 neuroblastoma patients. To validate those results, an additional 64 neuroblastoma tumors were also sequenced. The normal and tumor tissue samples were all donated by Memorial Sloan-Kettering Cancer Center patients. The human genome includes a chemical alphabet that stretches more than 3 billion characters in length and provides the instructions to build and sustain life.

The genome data from this and other published PCGP studies are available at no cost to the global scientific community at the PCGP Explore website. To access Explore, go to http://explore.pediatriccancergenomeproject.org.

Researchers found the ATRX gene was mutated in 44 percent of the 32 patients with neuroblastoma age 12 and older. The gene was altered in 17 percent of the 54 patients 18 months through 11 years, although the changes were found only in patients age 5 and older. None of the 18 patients in youngest treatment group, those age 17 months and younger, had ATRXmutations.

Although this is the first study linking changes in ATRX to neuroblastoma, mutations in the gene have been found in cancers of the pancreas, kidney and ovaries. In pancreatic neuroendocrine tumors, patients with ATRX mutations have a better prognosis while neuroblastoma patients with the altered gene fall into the age group with a poor prognosis. The ATRX mutations associated with neuroblastoma include deletions in the gene not found in other tumors.

Evidence in this study suggests ATRX mutations contribute to neuroblastoma cell survival in several ways, including a mechanism called alternative lengthening of telomeres (ALT). Telomeres are the strands of DNA at the end of chromosomes that limit the number of times a cell can divide. By lengthening the telomere, ALT contributes to the unchecked cell division that is a hallmark of cancer and likely makes cancer cells less vulnerable to chemotherapy or radiation therapy. The human genome is encoded in DNA and organized into chromosomes.

Researchers suspect ATRX is also involved in regulating the activity of other genes through epigenetic mechanisms that alter gene activity without changing the underlying DNA sequence. This is in keeping with previous discoveries at St. Jude that retinoblastoma and glioma cancer progression may be driven by epigenetic processes.

The paper’s other first authors are Jinghui Zhang of St. Jude and Charles Lu ofWashington University. The other authors are Matthew Parker, Armita Bahrami, Alberto Pappo, Sara Federico, James Dalton, Jianmin Wang, Xiang Chen, Jared Becksfort, Jianrong Wu, Catherine Billups, David Ellison andJames Downing, all of St. Jude; Satish Tickoo, Adriana Heguy and Irene Cheung, all of Memorial Sloan-Kettering Cancer Center; and Li Ding, Bob Fulton, and Elaine Mardis, all of Washington University in St. Louis.

The research was funded in part by the Pediatric Cancer Genome Project, including Kay Jewelers, a lead project sponsor; the National Cancer Institute, the National Institutes of Health, the Catie Hoch Foundation, the Robert Steel Foundation and ALSAC.

Washington University School of Medicine

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to www.mskcc.org.

SOURCE St. Jude Children’s Research Hospital

Coming From A Cancer Mom

By: Heather Sullivan

Jack was diagnosed with this monster in 2009, since then our world has never been the same. When someone utters the word cancer to you, it sends chills down your spine. Imagine being a mom and hearing this. I am a stay at home mom with five children. We have one younger than Jack. I wrote this to help you through your journey with your child.

Cancer can do a lot of things! When we found out that Jack had cancer I told my husband we will not let cancer rule our lives. Sometimes in life you have to stand up and fight and don’t look back. We travel 700 miles one way for his treatments. We travel as a family so here are some tips on how to survive trips to the hospitals, and living outside your home.

1. Do not take one day for granted. Cancer can rear its ugly head at anytime! Every child is different and their cancer is unique to them.
2. Have FAITH! Without the faith we would not have gotten this far, you have to hold onto something in these trials.
3. Get SUPPORT! You need to have a support system in place. Sometimes you need a shoulder!
4. Plan ahead. We always pack to-go bags for the kids, it has their favorite candy, drink, something to do in the car, and a note telling them how special they are, and they are a big part of our family. You see, cancer just doesn’t affect one person, it affects all around us.
5. If you have to stay in a hotel, find one that is kid friendly and one that offers breakfast and perhaps a snack at dinner time. They are out there, you just need to look.
6. Don’t let the nurses push you around. My child has been through hell and back and doesn’t like to get poked. He would rather have the gas mask than be poked. We had one nurse argue with us, and I politely told her that we will come back a different day. At that point the Doctor walked in and said we could wait till he was asleep. Prolong the suffering if you can!
7. Let your child be a kid! Jack always comes out of the hospital with his IV; we try to do fun things that he will like, such a going to his favorite movie, or restaurant.
8. Bring pictures to put around the room if you will have an extended stay, this makes it more homey.
9. Reach out to the different organizations, there are a ton out there.
10. Participate in anything that will help with research for our children. Research saved us from five rounds of chemo.
Do not be afraid of your child’s diagnosis, this is not a death sentence. Just know that no matter what, someone out there has already walked down this path, and they want to reach out to you!

SCREW YOU CANCER!!!

By: Gen Chamblee

I used to see St. Jude’s commercials on tv and thought “I can’t imagine what those parents are going through.” All the kids had the same look to them. They were bald and had something in their eyes that said, “help me.” I never dreamed that my child would end up looking like one of those kids. I am guilty of being one of those people who says, “cancer won’t touch us, it won’t happen to my child.”

The cemetery where my husband’s father is buried has a section called “The Garden of Angels” and when ever we went to visit his father, I never wanted to drive past that area because of how sad it made me feel that all of those children were gone. Again, I couldn’t imagine. Now my precious daughter is buried there.

How surreal it is. It’s mind boggling how life happens.

I still can not believe Sierra is gone. Some days I wake up and expect to hear her sweet, little voice in her bedroom. But then reality hits me that I will never see her face again. Never hear her voice, never see her smile, never give her kisses again. Cancer ripped her away from me. At night all I can do is lay there and replay the moment she passed over and over in my head. It’s in every way possible, complete torture.

Every time I walk by her empty room, it feels like someone is stabbing me in the heart. I read about her and choke up. It is truly the worst thing that anyone can go through. She will forever be 2 1/2 yrs old. Her pictures on the wall will never change, and all I have are the memories in my mind.

So many have asked me how I can start up a foundation so soon after Sierra passed? How could I go through pictures of her and sit down to write out her story? That I must be so strong to be able to do such a thing. You want to know how I did it? I’m not strong, I’m angry. Furious. I have never been so mad in my life at anything as I am at cancer. It messed with the wrong family this time.

I want the world to know who my beautiful Sierra was. I don’t want another parent to feel the pain I feel. The agonizing, ruthless pain of losing a child.

I have become a different person since January of 2010. I was introduced to the world of childhood cancer in the worst possible way. And now it’s my turn to do as much as possible to open the eyes of everyone who thinks it can’t happen to their child. Because guess what? IT CAN.

Pumping pure poison into childrens’ growing bodies is appalling. But you know what? It’s one of the only choices you have when the Dr. says, “your child has cancer.”

It’s so hard to fathom that only 3% of Federal cancer research money goes to childhood cancer. Neuroblastoma gets even less than that. Every single day 46 kids are diagnosed with cancer and 7 of them day each day. Neuroblastoma kills 1 child every 16 hours. And all we can get is 3%? Are you freakin’ kidding me?

Why are people so hesitant to give? I donated to St Jude’s numerous times before Sierra was ever diagnosed.

Cancer has no rhyme or reason. It doesn’t discriminate. Not one single person in this world is safe from it. It destroys everything good in this world, and it doesn’t care how old you are or how much money you have.

I get so angry when I think about it. People don’t realize how prevalent cancer is among children. It’s a world that people don’t want to think about. But it’s time everyone wakes the hell up and opens their eyes. Kids do get cancer and kids do die from it.

No one knows what Sierra went through on a daily basis.

Imagine a little girl no heavier than 20 lbs, on a ventilator for 3 ½ months, receiving enough sedation to kill an adult, blood transfusions two times a day, numerous chest tubes, addicted to narcotics, endless x-rays, scans, and IV pokes. Close your eyes and imagine huge amounts of poison being pumped through her veins, and adult poison at that. We have children’s Tylenol and children’s Benedryl, but after all these years, there is no such thing as a children’t chemo drug. Then she went through 9 ½ hours of surgery to extract this horrible thing. She battled pneumonia, and terrifying blood infections. And let’s also mention that she coded on two different occasions. To think though, Sierra never made it to stem cell transplant, radiation or antibody treatment. There were SIX pages of side effects for ONE chemo drug.

These kids fight for their lives, and then have to worry that the cancer doesn’t relapse. If it doesn’t – they truly survived. But, it’s not over. Now every day for the rest of their lives, they have to counter act all of the side effects from treatment. And then on top of that, they still have to worry about secondary cancer. But you want to know what was truly amazing about Sierra and all of these children? They smile every step of the way.

Childhood cancer is real people. You don’t want to have to learn about it the hard way like I did. You don’t want wait & be holding your child in your arms as they draw their last breath to wake up and fight back.

It’s totally unacceptable.

My child was not one of the lucky ones. And unfortunately, many of them aren’t.

But are you ready to open your eyes?

SCREW YOU CANCER!!!

Top 10 Tips For Surviving The Hospital

By: Barb Kronback

You’ve got the deer in the headlight look. You’re on a rollercoaster that is traveling out of control. The bottom has fallen out of your life and it will never be normal again. These are all feelings you will experience when your child has been diagnosed with cancer. How do you survive?

These tips will help you start to get your feet under you again.

1. Swallow your pride and accept any and all offers of help, whether that is bringing your family meals, cleaning, taking care of siblings, or running errands. When someone asks you how they can help, be honest. Don’t say you are “alright”, because you’re not.

2. Purchase or have someone else get you a hanging shoe bag. Put sample sizes of your hygiene products in the pockets. Slippers, vitamins, hair brush, anything else you need on a daily basis, so that when you have to go to the ER in the middle of the night, everything is ready. Keep it in a suitcase that already packed so you don’t have to worry about packing. Have books and games also packed for your child and yourself.

3. To keep track of medications. Have a calendar and different stickers for each medicine. Put one on the bottle and then when you give that medicine, put the same sticker on the calendar. This makes it so much easier to keep track of all medications and not worry if you forgot a dose, or if someone else is helping. This way they will know what to do.

4. Try to have someone with you when you have meetings with the doctors. You will be on information overload and may have a hard time understanding everything they are throwing at you. More than likely you will be sleep deprived also, so this person can take notes and jot down questions for you. Ask questions about anything you don’t understand. There is no dumb question. Remember you know your child best and are their only advocate.

5. Take care of yourself! Sleep when your child is sleeping. Make sure you eat everyday. Now you probably won’t feel like eating or be hungry, but you need to force yourself to have something. If you get run down you won’t be any good for your child. Keep snacks in the room like trail mix, fresh fruit, cheese sticks or yogurt. These are things others can buy for you. Keep a notebook handy to jot down anything you think of so if someone asks what you need, you’ll have it handy.

6. It will be hard but BE POSITIVE! Don’t let negativity into your child’s room. If you cry (and you will) do it where your child won’t see you because it will just scare them even more. Remember Laughter Is The Best Medicine! Watch comedies or cartoons with your child, the more they laugh, the better they will feel.

7. Depending on your child’s age, let them have control of the TV remote. They have lost all control over their life, and this is one thing that will make them feel they have control over something. You’ll probably go insane watching Sponge Bob marathons, but it is so worth it to see the smile on your child’s face.

8. Don’t stay in your child’s room 24/7. Get out and take a walk. Talk to other parents and share encouragement and prayers. When able, let your child meet other kids so they don’t feel so alone.

9. Set up a Caring Bridge site as soon as possible or have someone do it for you. This is a site to journal your cancer journey for family and friends to read, so you don’t have to make or field a zillion phone calls everyday. (www.caringbridge.org)

10. Make sure you have your child’s favorite blanket, stuffed animals, toys or pjs with you whenever you go to the hospital. Pictures of family members help too. You want to give your child comfort.

Remember – cancer doesn’t affect just your child, it affects the whole family.