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New gene mutations for Wilms tumor found

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.

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.

source : http://www.sciencedaily.com/releases/2014/09/140905113651.htm

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Gene likely to promote childhood cancers pinpointed by researchers

“We and others have found that Lin28b — a gene that is normally turned on in fetal but not adult tissues — is expressed in several childhood cancers, including neuroblastoma, Wilms’ tumor and hepatoblastoma, a type of cancer that accounts for nearly 80 percent of all liver tumors in children,” said Dr. Hao Zhu, a principal investigator at CRI, and Assistant Professor of Pediatrics and Internal Medicine at UT Southwestern Medical Center. “In our study, we found that overproduction of Lin28b specifically causes hepatoblastoma, while blocking Lin28b impairs the cancer’s growth. This opens up the possibility that pediatric liver cancer patients could one day be treated without resorting to chemotherapy.”

Lin28b is an attractive therapeutic target in cancer because it is ordinarily only expressed in embryos, so blocking it in children should specifically hinder cancer growth without introducing many side effects.

Each year in the United States, 700 children are newly diagnosed with neuroblastoma, 500 with Wilms’ tumor and 100 with hepatoblastoma. At Children’s Medical Center in Dallas, more than 100 children have been treated for those three types of cancers over the last two years.

Previous studies found that Lin28b is a critical factor in stem cell and fetal tissue development, leading Dr. Zhu and his team to hypothesize that the same gene would play a significant role in the development of certain cancers.

“We looked at Lin28b in a multitude of ways in mice to study its effects on cancer, from increasing it significantly to deleting it,” said Dr. Zhu, co-senior author of the paper. “From this and earlier studies, it appears that Lin28b activates the metabolic pathways that provide the building blocks of growth for certain cancers.”

The next step for the Zhu lab is to establish whether genes related to Lin28b have similar effects on the development of cancer, and to determine if those genes might be more effective targets for potential therapies.

source : http://www.sciencedaily.com/releases/2014/08/140811125120.htm