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Study links NF1 mutations to GIST tumors, highlighting the need for genetic testing


A team of researchers at UC San Diego Moores Cancer Center (CA, USA) in collaboration with researchers from Memorial Sloan Kettering Cancer Center (NY, USA) and Fox Chase Cancer Center (PA, USA) have highlighted that a specific region of the small bowel, termed the duodenal-jejunal flexure shows a high frequency of gastrointestinal stromal tumors (GISTs) with mutations of the NF1 gene.

GISTs represent the most common type of sarcoma in the GI tract, with an annual incidence of 6.8 cases per million people in the United States. These tumors start in special cells in the wall of the GI tract, termed the interstitial cells of Cajal (ICCs). Acting as pacemakers of the GI tract, ICCs signal the muscles in the digestive system to contract through peristalsis, moving food and liquid through the system.

Approximately 30% of all GISTs occur in the small bowel which is divided into three distinct segments: the duodenum, jejunum and ileum. Most small bowel GISTs are associated with KIT mutations. However, subsets of GISTs have mutations in other genes, such as NF1. NF1 can be mutated either somatically or in the germline. Interestingly, patients with NF-1 are 34 times more likely to develop GIST than unaffected individuals.

“Where the duodenum transitions into the jejunum, we are finding an over-representation of NF1-mutated GIST,” commented corresponding author, Jason Sicklick (UC San Diego Moores Cancer Center).

“Genomic testing for some of these patients revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1,” explained Sicklick. “Anyone with a GIST should undergo tumor genetic testing. Currently only 8–15%of patients get tested. For those patients with NF1 mutations, there are implications for family members of patients who test positive for hereditary NF-1, as they also may be at increased risk of developing cancers, including GIST.”

NF-1 is a condition that occurs in one in 3000–4000 individuals worldwide and is characterized by changes in skin coloring and the growth of tumors along nerves in the skin, brain and other parts of the body, such as the GI tract. The signs and symptoms of this condition vary widely among affected persons.

“Patients with GIST should have their tumors profiled with next-generation sequencing panels,” concluded first author, Adam Burgoyne (UC San Diego Moores Cancer Center). “We are uncovering a subset of patients, including patients with mutations of KIT, who have downstream mutations that may render them insensitive to conventional targeted therapy.”

Ultimately, more than 95%of patients with drug-resistant GIST succumb to their cancer, highlighting the necessity for alternative therapeutic targets. Therefore, the team hopes to discover a more personalized approach to GIST tumors that become progressively resistant to treatment.

Sources: Burgoyne AM, De Siena M, Alkhuziem M et al. Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations. JCO Precision Oncology. DOI: 10.1200/PO.17.00014  [Epub ahead of print] (2017); Eurekalert release