Paired tumor-normal targeted sequencing supports clonal independence of multiple primary malignancies in patients with gastrointestinal stromal tumors.

The association between gastrointestinal stromal tumors (GIST) and multiple primary malignancies (MPM) is recognized, but its molecular basis has not been investigated. The institutional registry recorded 26,783 patients diagnosed between October 2006 and December 2020, of whom 69 had GIST. Of these, 33 consented to genetic analysis under a prospective biospecimen-collection program. We compared clinicopathological characteristics between patients with and those without MPM.

We performed paired tumor-normal targeted sequencing using an amplicon-based panel on GIST and MPM tissue from 18 patients, with matched peripheral blood as the germline reference. MPM occurred in 19 of 69 GIST patients (27.5%), ranking fourth among eight cancer types, after gastric (31.5%), colorectal (29.8%) and esophageal cancer (28.4%) in our institutional registry. Older age was the only factor significantly associated with MPM (median 77.0 vs. 65.0 years; p = 0.007). Among the 33 patients who consented to genetic analysis, 19 had MPM and 18 were evaluable for paired tumor-normal sequencing.

GISTs harbored KIT or PDGFRA mutations, whereas MPMs carried tumor type-specific driver alterations including TP53, APC, KRAS and PIK3CA. No shared somatic variants were detected within the limits of the targeted sequencing panel, supporting clonal independence between GIST and co-occurring malignancies irrespective of temporal classification. MPM frequently occur in patients with GIST and arise independently. Paired tumor-normal sequencing supports clonal independence between GIST and co-occurring malignancies in all evaluable cases, regardless of timing.

Age-appropriate cancer screening and careful evaluation for gastrointestinal malignancies may be considered, particularly in older patients with GIST.