Not all KIT 557/558 codons mutations have the same prognostic influence on recurrence-free survival: breaking the exon 11 mutations in gastrointestinal stromal tumors (GISTs)

Abstract

Background: Although the gastrointestinal stromal tumor (GIST) genotype is not currently included in risk-stratification systems, a growing body of evidence shows that the pathogenic variant (PV) type and codon location hold a strong prognostic influence on recurrence-free survival (RFS). This information has particular relevance in the adjuvant setting, where an accurate prognostication could help to better identify high-risk tumors and guide clinical decision-making. Materials and Methods: Between January 2005 and December 2020, 96 patients with completely resected GISTs harboring a KIT proto-oncogene receptor tyrosine kinase ( KIT) exon 11 PV were included in the study. We analyzed the type and codon location of the PV according to clinicopathological characteristics and clinical outcome; the metastatic sites in relapsed patients were also investigated. Results: Tumors harboring a KIT exon 11 deletion or deletion/insertion involving the 557 and/or 558 codons, showed a more aggressive clinical behavior compared with tumors carrying deletion/deletion/insertion in other codons, or tumors with duplication/insertion/single-nucleotide variant (SNV) (7-year RFS: 50% versus 73.1% versus 88.2%, respectively; p < 0.001). Notably, among 18 relapsed patients with 557 and/or 558 deletion or deletion/insertion, 14 patients (77.8%) harbored deletions simultaneously involving 557 and 558 codons, while only 4 patients (22.2%) harbored deletions involving only 1 of the 557/558 codons. Thus, when 557 or 558 deletions occurred separately, the tumor showed a prognostic behavior similar to the GIST carrying deletions outside the 557/558 position. Remarkably, patients with GISTs stratified as intermediate risk, but carrying the 557/558 deletion, showed a similar outcome to the high-risk patients with tumors harboring deletions in codons other than 557/558, or duplication/insertion/SNV. Conclusion: Our data support the inclusion of the PV type and codon location in routine risk prediction models, and suggest that intermediate-risk patients whose GISTs harbor 557/558 deletions may also need to be treated with adjuvant imatinib like the high-risk patients.

Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study

“…Our result is not consistent with Incorvaia et al’s result. Although several study groups have reported the poor prognostic role of D-557/8 or deletion in c-KIT exon 11 on recurrence free survival in resected GIST patients, the impact of mutational type of c-KIT exon 11 on survival of advanced GIST patients needs more data for further confirmation [ 32 – 34 ]. The genetic study for c-KIT and PDGFRA is not routinely performed for GISTs because it is not reimbursed in Taiwan and the application of sunitinib or regorafenib is feasible without genetic data.…”

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors

“…The type of GIST driver mutation represents an important prognostic factor, correlating with clinical features and biological aspects of the disease [5]. The presence of deletions within c-KIT codons 557/558 is associated with a more aggressive behavior compared to other exon 11 mutations, thus resulting in shorter recurrence-free survival (RFS) for patients with resected GIST and shorter PFS for metastatic patients [44,45].…”

“…Immune checkpoints, such as PD-L1, PD-1, and CTLA-4, by escaping immune surveillance, play a key role in tumor progression and influence the survival of patients with solid tumors [16,47]. According to the recent knowledge, despite some known limitations, immune checkpoint expression could be a potential prognostic factor and predictive biomarker of response to immune checkpoint inhibitors in patients with solid tumors [45,[48][49][50][51].…”

Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors HarboringKITExon 11 557–558 Deletion Mutations

“…GISTs carrying KIT exon 11 mutations with deletions at codon 557 and/or 558 have a poorer prognosis than those with mutations at other sites ( 6–9 ). Deletions at both codons 557 and 558 promote liver metastasis ( 10 ) and are thought to be required for malignant transformation ( 11 ). The malignant progression of GISTs has also been associated with chromosomal changes, including deletions in chromosome arms 1p, 13q, 14q, 15q, and 22q; gains in chromosomes 4 and 5 ( 12–14 ); and genetic alterations, including mutations, copy-number (CN) abnormalities, and aberrant expression of cell cycle–related genes ( p53 , CDKN2A , and RB1 ; ref.…”