RARE MUTATIONS IN GISTs

NEW YORK (Reuters Health) - A report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic is shedding more light on the molecular subtypes of gastrointestinal stromal tumors (GISTs).

In particular, the team examined the wild type, which lacks KIT and PDGFRA gene mutations, and is most commonly found in children.

As Dr. Lee J. Helman told Reuters Health by email, "The NIH Clinical Center is an ideal setting to bring rare tumors to study -- we accumulated the largest (hitherto assembled) number of WT GIST patients over a few years."

In a March 24 online paper in JAMA Oncology, Dr. Helman, of the National Cancer Institute, Bethesda, Maryland, and colleagues reported that they recruited 116 patients with WT GIST of whom 95 had adequate tumor specimen.

Tumors were characterized by immunohistochemical analysis for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation.

In all, 84 patients had SDH-deficient GIST (75% due to SDH mutations and 25% to SDHC promoter hypermethylation), and 18 had syndromic GIST with chondromas and/or paragangliomas.

Thus, continued Dr. Helman, "The vast majority of young GIST patients with no KIT or PDGFRA mutations were found to have SDH-deficient tumors caused by mutations in SDH A, B, C or D, or hypermethylation of the SDHC promoter."

"Most SDH mutations are germline," he added, "and require search for germline mutations, which may require genetic counseling, while hypermethylation of SDHC promoter is not inheritable and therefore does not require genetic counseling."

Overall, Dr. Helman concluded, "We hope that the identification of SDH deficiency as the driver of these GIST tumors will lead to new therapeutic interventions that have the possibility to be more effective than currently available treatment."

Commenting on the findings by email, Dr. Heikki Joensuu of the University of Helsinki, Finland, told Reuters Health that this is the first comprehensive analysis of such GISTs.

"The study is very important," he said, "as the investigators were able to develop a meaningful molecular classification for these rare tumors that has strong clinical correlates."

"The study," he continued, "demonstrates the usefulness of carrying out immunohistochemical staining for SDHB when mutation analysis of KIT and PDGFRA is negative. In addition, sequencing of the four SDH genes . . . can now be recommended, as well as SDHC promoter methylation analysis. The treatment of patients with advanced SDH-deficient GIST remains a challenge, but we can now better identify patients who benefit from further molecular testing, screening for tumors that are linked with SDH-deficient GISTs, and identify patients who benefit from genetic counseling."

Dr. Joensuu, who conducts research in the field, concluded, "Very importantly the study shows that the strategy of founding a highly specialized clinic for patients with a rare type of cancer can be highly successful. Other nations should now follow the U.S. example."

The National Cancer Institute funded this research. The authors made no disclosures.

SOURCE: http://bit.ly/1qlltoz

JAMA Oncol 2016.