A recently published study in NPJ Precision Oncology has suggested that all patients with KIT/PDGFRA-wildtype gastrointestinal stromal tumors (GISTs) should be offered germline testing regardless of their syndromic features history.

The study also suggested that identifying pathogenic/likely pathogenic (P/LP) variants in unspecified genes in tumor-only sequencing of GISTs might indicate germline testing.

Gastrointestinal stromal tumors are the most prevalent mesenchymal tumors of the gastrointestinal system. Most (85–90%) GISTs possess activating mutations in either KIT or PDGFRA genes. The contribution of germline variants to GIST development remains to be fully characterized because of the limited pre-selection of patients and genes for genetic testing.

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To investigate if more extensive genetic testing of GIST patients without pre-selection could reveal those individuals with a hereditary predisposition, the researchers analyzed the sequencing results of tumors and germline DNA from 103 patients treated at Memorial Sloan Kettering (MSK) Cancer Center over 6 years. The testing was done using MSK Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), which included 76-90 genes related to cancer predisposition. Furthermore, the research team investigated 499 de-identified tumor-normal pairs to assess the frequency of somatic versus germline variants detected in tumor-only sequencing of GISTs.

Study results showed that of the 103 patients, 23% reported a germline P/LP variant in the GIST-associated gene, while an additional 8% of patients demonstrated a germline P/LP variant in a different cancer susceptibility gene, which suggested that all the patients with GIST, regardless of their tumor testing status, can get benefit from germline testing.

Additionally, germline P/LP variants in GIST-associated genes, including SDHA, SDHB, SDHC, NF1, and KIT, were detected in 69% of patients experiencing KIT/PDGFRA-wildtype GISTs, while 63% of them have no personal or family history of syndromic features.

Moreover, study results related to the analysis of tumor-normal pairs suggested that identifying P/LP variants in specific genes in the tumor-only sequencing of GISTs might signify germline testing. Besides, P/LP variants in specific genes such as BRCA1/2 and SDHB, identified in tumor-only sequencing of GISTs, were reported to be almost exclusively germline in their origin.

Further large-scale studies on the phenotypic spectrum of GIST-associated genes might help formulate clinical guidelines for expanded genetic testing in patients with GIST.

The authors noted several limitations in the study, including the detailed clinical assessments, which were only performed on 103 patients who consented to the germline testing, and the possibility of not detecting specific variants like structural variants or low-level mosaicism.

“Despite these limitations, our results support that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs, regardless of their history of syndromic features, and should target all GIST-associated genes at minimum,” the authors concluded.


Mandelker D, Marra A, Mehta N, et.al. Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterationsNPJ Precis Oncol. Published online January 2, 2023. doi: 10.1038/s41698-022-00342-z