Lack of microsatellite instability in gastrointestinal stromal tumors

Abstract

The microsatellite instability (MSI) phenotype may constitute an important biomarker for patient response to immunotherapy, particularly to anti-programmed death-1 inhibitors. MSI is a type of genomic instability caused by a defect in DNA mismatch repair (MMR) proteins, which is present mainly in colorectal cancer and its hereditary form, hereditary nonpolyposis colorectal cancer. Gastrointestinal stromal tumor (GIST) development is associated with activating mutations of KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor α (PDGFRA), which are oncogenes that predict the response to imatinib mesylate. In addition to KIT/PDGFRA mutations, other molecular alterations are important in GIST development. In GISTs, the characterization of the MSI phenotype is scarce and the results are not consensual. The present study aimed to assess MSI in a series of 79 GISTs. The evaluation of MSI was performed by pentaplex polymerase chain reaction comprising five markers, followed by capillary electrophoresis. The expression of MMR proteins was evaluated by immunohistochemistry. Regarding the KIT/PDGFRA/B-Raf proto-oncogene, serine/threonine kinase molecular profile of the 79 GISTs, 83.6% of the tumors possessed KIT mutations, 10.1% had PDGFRA mutations and 6.3% were triple wild-type. The mutated-PDGFRA cases were associated with gastric location and a lower mitotic index compared with KIT-mutated and wild-types, and these patients were more likely to be alive and without cancer. MSI analysis identified 4 cases with instability in one marker, however, additional evaluation of normal tissue and immunohistochemical staining of MMR proteins confirmed their microsatellite-stable nature. The results of the present study indicated that MSI is not involved in GIST tumorigenesis and, therefore, cannot serve as a biomarker to immunotherapy response in GIST.

Rare Occurrence of Microsatellite Instability in Gastrointestinal Stromal Tumors

“…Moreover, MSICall only used the sequencing data of the tumor and baseline control samples, which required less computer resources and could reduce turnaround times. Similarly to previous reports [ 1 , 21 ], all of our GIST patients showed MSS status, which confirmed that MSI status did not participate in the molecular pathogenesis of GISTs. Campanella et al reported that the features of the MSI phenotype are not sufficient, and this is thus not a biomarker for the immunotherapy response in GISTs [ 1 ].…”

“…Similarly to previous reports [ 1 , 21 ], all of our GIST patients showed MSS status, which confirmed that MSI status did not participate in the molecular pathogenesis of GISTs. Campanella et al reported that the features of the MSI phenotype are not sufficient, and this is thus not a biomarker for the immunotherapy response in GISTs [ 1 ]. MSI is not associated with the degree of malignancy or the p53 expression of GISTs [ 21 ].…”

“…Thus, the determination of MSI status has crucially aided treatment plans and clinical prognoses in various solid tumors, and plays a key role in good responses to immunotherapy in solid tumors with dMMR and high MSI [ 19 , 20 ]. However, high MSI status was not shown to be involved in GIST tumorigenesis [ 1 ], or in the degree of malignancy and the p53 expression of GISTs [ 21 ]. It was also shown that the mechanisms and functions of the MMR system were accomplished in patients with GISTs.…”

“…Microsatellites are repetitive tracts in certain DNA motifs, ranging from one to six or more nucleotide pairs in length [ 1 ]. Replication slips are recognized and repaired through the DNA mismatch repair (MMR) system, such as with MSH6, MLH1, MSH2, and PMS2, to conserve cellular homeostasis [ 2 ].…”

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor

“…Similarly, PDGFRA-mutant GISTs had higher CD4, CCR4, and CCR5 expression (indicative of regulatory T cells) and higher expression of the immunomodulators BTLA, CD48, TNFRSF9, and TIGIT. PDGFRA-mutant GISTs, there- has been shown to have a lower proliferative index when compared with KIT-mutant GIST (46). However, when controlling for mutational driver, the relationship between mitotic rate and immune cell infiltration in UPG GISTs loses significance, suggesting that oncogenic driver may be more important for dictating the immune infiltrate.…”