Molecular Subtyping of Pediatric Gastrointestinal Stromal Tumors Allows For Refined Treatment and Genetic Counseling

MedicalResearch.com Interview with:

Lee J. Helman, MD Senior Investigator Pediatric Oncology Branch Head, Molecular Oncology Section Acting Director, Center for Cancer Research and CCR Scientific Director for Clinical Research National Cancer Institute Bethesda, Maryland

Dr. Lee Helman

Lee J. Helman, MD
Senior Investigator
Pediatric Oncology Branch
Head, Molecular Oncology Section
Acting Director, Center for Cancer Research and
CCR Scientific Director for Clinical Research
National Cancer Institute
Bethesda, Maryland

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Helman: It was known that most gastrointestinal stromal tumors (GISTS) that occur in children and young adults do not contain cKIT or PDGFRA mutations that drive more than 90% of adult GIST tumors.  Since GISTs are quite rare in the pediatric and young adult population, we decided to establish a clinic at NIH that would allow us to study the most patients to try to define these tumors both clinically and molecularly. We were able to bring both patients and physicians interested in pediatric GIST from around the country to the NIH to begin to collect and study these patients. Of the 95 patients in this cohort study that lacked cKIT or PDGFRAmutations, 84 were found to have succinate dehydrogenase (SDH) deficient (SDH-deficient) GIST (75% due to SDH A, B, C, or mutations, and 25% due to SDHC promoter hypermethylation. Since these tumors are driven by SDH loss and not due to KIT or PDGFR mutations, they do not generally respond to standard treatments for GIST that target these kinases.

The mechanism of SDH-deficiency is important, since SDH mutations are commonly germ line and therefore require genetic counseling and family testing, while the SDHC promoter methylation is not a germ line alteration and therefore does not require genetic counseling.  Finally, any patient with SDH-deficient GIST is also at risk for development of paraganglioma and should be screened on a regular basis for these tumors. 

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Helman: Patients younger than 30 with a gastric GIST that is not cKIT or PDGFRA mutated should be tested for SDH loss in their tumor by immunohistochemistry (IHC) for SDHB.  If SDHB is absent by IHC, the tumor should be analyzed by capture sequencing to identify specific SDH mutations.  If no SDH mutation is identified, the SDHC promoter should be tested for hypermethylation.  Based on these results, appropriate counseling and recommendations for care and counseling can be made.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Helman: We have found that the SDH-deficient GIST tumors all have prominent global DNA hypermethylation as a direct result of the SDH alterations.  Future research is aimed at determining whether demethylating agents may offer therapeutic benefit.  Further studies are also aimed at defining risks for both GIST outcome and risk of paragangliomas based on genetic alterations.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Boikos SA, Pappo AS, Killian J, et al. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. Published online March 24, 2016. doi:10.1001/jamaoncol.2016.0256.

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