New gene for childhood cancer neuroblastoma is discovered

December 01, 2010

Pediatric cancer researchers have identified variations in a gene as important contributors to neuroblastoma, the most common solid cancer of early childhood. The study team, led by researchers at The Children's Hospital of Philadelphia, found that common variants in the LMO1 gene increase the risk of developing an aggressive form of neuroblastoma, and also mark the gene for continuing to drive the cancer's progression once it forms.

The study appears online today in Nature. A cancer of the sympathetic nervous system that usually occurs as a solid tumor in the abdomen, neuroblastoma accounts for 10 percent of childhood cancer deaths.

"Although genes closely related to LMO1 have previously been implicated in other cancers, this gene was not previously suspected to have a role in neuroblastoma," said study leader John M. Maris, M.D., director of the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia. "We found that in addition to putting a child at risk of developing neuroblastoma, it acts as an oncogene--driving the biological changes that make tumors grow and spread throughout the body."

Although direct clinical applications are not immediate, Maris added, investigating this oncogene may suggest targets for developing more effective neuroblastoma treatments.

Maris collaborated with Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia, and co-senior author on the study, as well as with a large team of international investigators in performing a genome-wide association study (GWAS). They analyzed DNA samples from 2,251 patients (most of which were provided by the multicenter Children's Oncology Group) along with 6,097 control samples.

The researchers found a significant association between neuroblastoma and the LMO1 gene, located on chromosome 11, detecting the strongest signal among patients with the most aggressive form of the disease. This portion of the study identified SNPs, changes in a single letter within the DNA sequence, which predispose a child to developing neuroblastoma.

The study team then searched for copy number alterations--duplications or deletions of stretches of DNA--across the whole genome in neuroblastoma cancer cells. Again, the LMO1 gene displayed abnormal changes: duplicated sections of DNA that tended to occur in a significant percentage of tumors.

"The normal role of the LMO1 gene is mainly to regulate gene transcription in the nervous system," said Maris. In gene transcription, DNA-encoded information is converted to RNA, part of the process by which a gene carries out biological functions. "The abnormalities we have found in this gene result in abnormally increased activity, driving an overproduction of cells into a tumor."

To further investigate the gene's role, the researchers used genetic tools to decrease LMO1's activity, and showed that this inhibited the growth of neuroblastoma cells in culture. Increasing LMO1 gene expression had the opposite effect, causing tumor cells to proliferate.

Because other genes in the LMO family are known to be active in acute leukemias, other researchers have been investigating potential anti-leukemia drugs to target portions of the LMO pathway. However, added Maris, using this knowledge to develop treatments for either leukemia or neuroblastoma will require much further work.

In the meantime, Maris suggests, the current research suggests that GWAS studies, already widely employed to identify common gene variants that confer disease risk, may also have another benefit, in indicating that the same genetic region may have a strong impact on cancer progression. "The real potential of studies like this may be in discovering new therapeutic targets."

Hakonarson agrees, adding that, "This is a prime example in which integrative genomics, combining SNP discovery arrays with gene expression arrays and other functional approaches, holds great promise in expanding our knowledge base for translating genetic discovery to clinical uses."
-end-
The Children's Oncology Group provided the majority of blood and tumor specimens, as well as clinical and outcome data, used in the study. Financial support for the study came from the National Institutes of Health, The Children's Hospital of Philadelphia, the Giulio D'Angio Endowed Chair, the Alex's Lemonade Stand Foundation, the Evan Dunbar Foundation, the Rally Foundation, Andrew's Army Foundation, the Abramson Family Cancer Research Institute, a Howard Hughes Medical Institute Research Training Fellowship, a fellowship from Associazione Oncologia Pediatrica e Neuroblastoma, and the Cotswold Foundation.

Collaborating with The Children's Hospital of Philadelphia researchers were researchers from the University of Pennsylvania; the Institute of Cancer Research in Surrey, UK; the National Cancer Research Institute, Tokyo; CEINGE Biotecnologie Avanzate, Naples, Italy; the University La Sapienza, Rome; the University of Florida, Dana-Farber Children's Hospital Cancer Center, Boston; and the University of Naples Federico II.

"Integrative Genomics Identifies LMO1 as a Neuroblastoma Oncogene," Nature, published online Dec. 1, 2010. DOI: 10.1038/nature09609

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 460-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Children's Hospital of Philadelphia

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.