Monthly Archives: April 2014

A new study shows that a gene discovered 30 years ago and now known to play a fundamental role in cancer development produces five different gene variants (called isoforms), rather than just the one original form, as thought.

The study of the NRAS gene by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) identified four previously unknown variants that the NRAS gene produces.

The finding might help improve drugs for cancers in which aberrant activation of NRAS plays a crucial role. It also suggests that NRAS might affect additional target molecules in cells, the researchers say.

The isoforms show striking differences in size, abundance and effects. For example, the historically known protein (isoform 1) is 189 amino-acids long, while one of the newly discovered variants, isoform 5, is only 20 amino-acids long.

The study is published in the Proceedings of the National Academy of Sciences.

"We believe that the existence of these isoforms may be one reason why NRAS inhibitors have so far been unsuccessful," says corresponding author Albert de la Chapelle, MD, PhD, professor of Medicine and the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research.

Co-senior author Clara D. Bloomfield, MD, Distinguished University Professor and Ohio State University Cancer Scholar, notes that one of the newly discovered isoforms might play a greater role in the development of some cancers than the known protein itself.

"Targeting the NRAS pathway may have been unsuccessful in the past because we were unaware of the existence of additional targets of these novel isoforms," says Bloomfield, who is also senior adviser to the OSUCCC -- James and holds the William Greenville Pace III Endowed Chair in Cancer Research.

"The discovery of these isoforms might open a new chapter in the study of NRAS," says first author Ann-Kathrin Eisfeld, MD, a postdoctoral fellow in the laboratories of de la Chapelle and of Bloomfield. "Knowing that these isoforms exist may lead to the development of drugs that specifically decrease or increase the expression of one of them and provide more effective treatment for cancer patients."

For this study, de la Chapelle, Eisfeld and their colleagues analyzed expression of the NRAS isoforms in a variety of normal and matched tumor samples. Key technical findings include:

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Well-known cancer gene NRAS produces 5 variants, study finds

PUBLIC RELEASE DATE:

6-Apr-2014

Contact: Carrie Strehlau carrie.strehau@stjude.org 901-595-2295 St. Jude Children's Research Hospital

(MEMPHIS, TENN. - April 6, 2014) The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project has identified new mutations in pediatric brain tumors known as high-grade gliomas (HGGs), which most often occur in the youngest patients. The research appears today as an advance online publication in the scientific journal Nature Genetics.

The discoveries stem from the most comprehensive effort yet to identify the genetic missteps driving these deadly tumors. The results provide desperately needed drug development leads, particularly for agents that target the underlying mutations. This and other studies show these mutations often differ based on patient age. HGGs represent 15 to 20 percent of brain and spinal tumors in children. Despite aggressive therapy with surgery, radiation and chemotherapy, long-term survival for HGG patients remains less than 20 percent.

The study is one of four being published simultaneously in the same issue of Nature Genetics that link recurring mutations in ACVR1 to cancer for the first time. Pediatric Cancer Genome Project researchers found that ACVR1 was mutated in 32 percent of 57 patients diagnosed with a subtype of HGG called diffuse intrinsic pontine glioma (DIPG). While DIPGs are usually found in children ages 5 to 10, ACVR1 mutations occurred most frequently in younger-than-average patients. DIPG occurs in the brainstem, which controls vital functions and cannot be surgically removed.

The investigators also identified alteration in NTRK genes that drove tumor development in young HGG patients whose tumors developed outside the brainstem. This study included 10 patients who were age 3 or younger when they were diagnosed with such non-brainstem HGGs. Of those, 40 percent had tumors with alterations in one of three NTRK genes and few other changes. The alterations occurred when a segment of the NTRK genes involved in regulating cell division fused with part of another gene.

"These results indicate the NTRK fusion genes might be very potent drivers of cancer development that have the ability to generate tumors with few other mutations," said co-corresponding author Suzanne Baker, Ph.D., a member of the St. Jude Department of Developmental Neurobiology. The other corresponding author is Jinghui Zhang, Ph.D., a member of the St. Jude Department of Computational Biology. "We want to see if these tumors might be selectively sensitive to therapies that target the pathways that are disrupted as a result of these fusion genes," Baker said.

Added co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis: "We've made some very exciting discoveries that likely will result in more effective diagnosis and treatment of these particularly nasty tumors."

In this study, researchers analyzed 127 HGGs from 118 pediatric patients, including whole genome sequencing of the complete tumor and normal DNA from 42 patients. More targeted sequencing of additional tumors was conducted to track how instructions encoded in DNA were translated into the proteins that do the work of cells.

Original post:
Gene sequencing project discovers mutations tied to deadly brain tumors in young children