Researchers Find New Gene Mutations for Wilms Tumor

Newswise — DALLAS – Sept. 5, 2014 – Researchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.

Wilms tumor is the most common childhood genitourinary tract cancer and the third most common solid tumor of childhood.

“While most children with Wilms tumor are thankfully cured, those with more aggressive tumors do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumor patients. We wanted to know – what are the genetic causes of Wilms tumor in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.

Dr. James Amatruda with UT Southwestern faculty members.

Dr. James Amatruda with UT Southwestern faculty members.

The new findings appear in Nature Communications. Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.

Previous research has identified one or two mutant genes in Wilms tumors, but only about one-third of Wilms tumors had these mutations.

“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumors and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”

“Let-7 is an important microRNA that slows cell growth and in Wilms tumors in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.

These findings have implications for future treatment of Wilms tumor and several other childhood cancers, including neuroblastoma, germ cell tumor, and rhabdomyosarcoma.

“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumors. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumor looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. This study also is a gratifying example of great teamwork. As oncologists, Dr. Chen and I were able to make rapid progress by teaming up with Dr. Rakheja, an expert pathologist, and with Dr. Mendell, a leading expert on microRNA biology.”

According to the American Cancer Society, an estimated 510 cases of Wilms tumor will be diagnosed among children in 2014. Also called nephroblastoma, Wilms tumor is an embryonal tumor of the kidney that usually occurs in children under age 5, and 92 percent of kidney tumors in this age group are Wilms tumor. Survival rates for Wilms tumor have increased from 75 percent in 1975-1979 to 90 percent in 2003-2009.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 91,000 hospitalized patients and oversee more than 2 million outpatient visits a year.


Media Contact: Lori Sundeen Soderbergh

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Dr. James F. Amatruda: a recognized leader and innovator in pediatric germ cell research.

Assistant Professor of Pediatrics, Molecular Biology and Internal Medicine, UT Southwestern Medical Center. Attending Physician, Center for Cancer and Blood Disorders, Children’s Medical Center

A recognized leader and innovator in pediatric germ cell research, Dr. James F. Amatruda is the head of the Germ Cell Tumor Biology Committee for the Children’s Oncology Group, a national organization that treats every pediatric patient in the Unites States affected by germ-cell tumors. Amatruda has earned recognition for his discovery of a gene mutation in zebrafish (small aquarium fish with human-like genes that allow scientists to identify triggers and observe how cancers grow and spread) that causes tumors in germ cells. Such tumors can be the source of testicular cancer, ovarian cancer and other pediatric tumors. The discovery of the gene mutation has been hailed as a significant breakthrough in pediatric cancer research because germ-cell tumors are unusual in their composition, and their understanding among the scientific community is still limited.

Dr. James F. Amatruda

Dr. James F. Amatruda

WHY HEALTH CARE: My father was a big influence. He was an old-fashioned doctor who was devoted to, and loved by, his patients. I have been interested in science since I was a boy. When I was in college, I volunteered at a local homeless shelter, accompanying people to the hospital for their appointments. That really opened my eyes to the power of medicine to relieve suffering.

YOUR WORK: I am a specialist in pediatric cancer. I divide my time between Children’s and my lab at UT Southwestern, where we are focused on developing better treatments for childhood cancers. We focus on two types of childhood cancers: germ-cell tumors of the ovary and testis, and Ewing’s Sarcoma, a bone cancer. We have a strong belief that the best way to improve our treatments is to really understand the “wiring diagram” of the tumor cells. What makes a cancer cell different from a normal cell? What are its weaknesses, and how can we exploit these to develop treatments that will kill the cancer cells but not harm the normal tissue?

PROUD MOMENT: What makes our work fairly unique is that we use the small aquarium fish, zebrafish, to model human cancer. Zebrafish develop the same types of cancers that humans do, but they are small, easy to maintain, and grow fast, so we can do large-scale experiments to look at thousands of genes that might affect cancer. Recently, we identified a gene family that, when defective, causes germ-cell tumors in the fish. With this clue, we have been looking at germ-cell tumors from kids and find that the same genes are altered. This is exciting because for the first time we can think about making better treatments for germ-cell tumors that are specific for the cancer cells.

BIGGEST CHALLENGE: Childhood cancer does not get the attention it deserves. Overall, cancers in kids are rare. This is a good thing of course, but it means that, compared with adult cancers, pediatric cancers get little attention or funding from grant agencies or the pharmaceutical industry. The rarity of the tumors also means that we have to work together with physicians and scientists from around the world to pool our results. We’re now working with the Children’s Oncology Group, a national organization of pediatric cancer specialists, to study a collection of several hundred cancer specimens from patients with germ-cell tumors.

SUPPORT TEAM: I’ve been extremely lucky to benefit from the generosity of the fantastic philanthropic community here in Dallas. Two organizations, The Children’s Cancer Fund and Wipe Out Kid’s Cancer, work tirelessly to support children’s cancer research. Work in my lab has been directly supported by the American Cancer Society, the Amon G. Carter Foundation and Kevin’s Ewing’s Sarcoma Fund.

ULTIMATE CAREER GOAL: There is a lot of reason for hope in childhood cancer. Overall, 75 percent of children diagnosed with cancer will be cured of their disease. But we will never rest until that number is 100%. We also know that our current treatments, even when effective, have far too many side effects, which can cause long-term problems. So we have to keep working to truly understand the causes of childhood cancer, and to develop treatments that are more effective and less toxic. I feel very fortunate to be in this field at such an exciting time, and I am continually inspired by the courage of the children and families I meet. To me, they are the real heroes in this story.