New gene fusions and mutations linked to gastrointestinal stromal tumors

December 15, 2016

In recent years, researchers have identified specific gene mutations linked to gastrointestinal stromal tumors (GIST), which primarily occur in the stomach or small intestine, with 5,000 to 6,000 new cases per year in the United States.

But 10 to 15 percent of adult GIST cases and most pediatric cases lack the documented tell-tale mutations, making identification and treatment more difficult. In their paper published online Dec. 14 in the Journal of Translational Medicine, researchers at University of California San Diego School of Medicine and Moores Cancer Center have identified new gene fusions and mutations associated with this subset of GIST patients.

"We are continuing to slice the GIST pie into thinner pieces based upon identifying new driver genes," said Jason Sicklick, MD, associate professor of surgery at UC San Diego School of Medicine and surgical oncologist at Moores Cancer Center at UC San Diego Health. "This will allow for a more personalized approach to treating GIST patients."

Sicklick and colleagues are leading efforts to diagnose and treat GIST, which originates in special cells that signal muscles to contract, moving food and liquid through the digestive system. Many current therapies for GIST are ineffective in patients whose tumors lack mutations in the classic oncogenic drivers of GIST. Ultimately, more than 95 percent of patients eventually succumb to drug-resistant GIST, highlighting the necessity for alternative therapeutic targets.

Treatment with imatinib (marketed as Gleevec) has proven effective in many GIST cases associated with KIT oncogene mutations, the most common driver of the disease. Building upon that success and approach, Sicklick's team, which included collaborators in Oregon, Texas, Massachusetts, Pennsylvania, Florida and South Korea, used broad genomic sequencing of GIST patients without KIT or other documented mutations to identify alterations in at least two new genes: FGFR1 and NTRK3. "Broad genomic sequencing was critical to expand our search beyond the KIT mutations streetlight" says Olivier Harismendy, PhD, head of the oncogenomics laboratory at Moores Cancer Center, referring to observational bias of previous studies.

"These findings provide novel insights into the biology of the disease and new potential genetic drivers," Sicklick said. "With further studies, we can build an even more complete genetic profile of GIST, which in turn can lead to new individualized treatments and better outcomes for more GIST patients. For example, one patient in this study had an ETV6-NTRK3 mutant GIST and responded to a matched therapy with Loxo-101, a highly selective TRK inhibitor, after progressing on several earlier lines of FDA-approved therapies for GIST."
-end-
Co-authors of the study include: Eileen Shi, Chih-Min Tang, Katherine E. Fero, James D. Murphy, Paul T. Fanta, Martina De Siena, Adam M. Burgoyne, Lisa Madlensky, Gregory M. Heestand, and Razelle Kurzrock, UC San Diego Moores Cancer Center; Juliann Chmielecki, Kai Wang, Siraj M. Ali, Deborah Morosini, and Jeffrey S. Ross, Foundation Medicine Inc.; Michael C. Heinrich, Portland VA Health Care System; Guhyun Kang, and Christopher L. Corless, Oregon Health Sciences University; David Hong, University of Texas MD Anderson Cancer Center; Sujana Movva, Fox Chase Cancer Center; and Jonathan C. Trent, University of Miami Sylvester Cancer Center.

University of California - San Diego

Related Disease Articles from Brightsurf:

CLCN6 identified as disease gene for a severe form of lysosomal neurodegenerative disease
A mutation in the CLCN6 gene is associated with a novel, particularly severe neurodegenerative disorder.

Cellular pathway of genetic heart disease similar to neurodegenerative disease
Research on a genetic heart disease has uncovered a new and unexpected mechanism for heart failure.

Mechanism linking gum disease to heart disease, other inflammatory conditions discovered
The link between periodontal (gum) disease and other inflammatory conditions such as heart disease and diabetes has long been established, but the mechanism behind that association has, until now, remained a mystery.

Potential link for Alzheimer's disease and common brain disease that mimics its symptoms
A new study by investigators from Brigham and Women's Hospital uncovered a group of closely related genes that may capture molecular links between Alzheimer's disease and Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, a recently recognized common brain disorder that can mimic Alzheimer's symptoms.

Antioxidant agent may prevent chronic kidney disease and Parkinson's disease
Researchers from Osaka University developed a novel dietary silicon-based antioxidant agent with renoprotective and neuroprotective effects.

Tools used to study human disease reveal coral disease risk factors
In a study published in Scientific Reports, a team of international researchers led by University of Hawai'i (UH) at Mānoa postdoctoral fellow Jamie Caldwell used a statistical technique typically employed in human epidemiology to determine the ecological risk factors affecting the prevalence of two coral diseases--growth anomalies, abnormalities like coral tumors, and white syndromes, infectious diseases similar to flesh eating bacteria.

Disease-aggravating mutation found in a mouse model of neonatal mitochondrial disease
The new mitochondrial DNA (mtDNA) variant drastically speeds up the disease progression in a mouse model of GRACILE syndrome.

Human longevity largest study of its kind shows early detection of disease & disease risks
Human Longevity, Inc. (HLI) announced the publication of a ground-breaking study in the journal Proceedings of the National Academy of Sciences (PNAS).

30-year study identifies need of disease-modifying therapies for maple syrup urine disease
A new study analyzes 30 years of patient data and details the clinical course of 184 individuals with genetically diverse forms of Maple Syrup Urine Disease (MSUD), which is among the most volatile and dangerous inherited metabolic disorders.

Long-dormant disease becomes most dominant foliar disease in New York onion crops
Until recently, Stemphylium leaf blight has been considered a minor foliar disease as it has not done much damage in New York since the early 1990s.

Read More: Disease News and Disease 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.