Tumor genotype, location, and malignant potential shape the immunogenicity of primary untreated gastrointestinal stromal tumors

Gasparotto, Daniela; Sbaraglia, Marta; Rossi, Sabrina; Baldazzi, Davide; Brenca, Monica; Mondello, Alessia; Nardi, Federica; Racanelli, Dominga; Cacciatore, Matilde; Tos, Angelo Paolo Dei; Maestro, Roberta

doi:10.1172/jci.insight.142560

Cited by 12 publications

(30 citation statements)

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“…Finally, the authors found that the D842V mutation produces more high-affinity neoepitopes, binding with many prevalent HLA types, which suggests that the presence of this mutation could be involved in immune responses in a wide variety of patients [37]. [36][37][38]. Abbreviations: GIST: gastrointestinal stromal tumors; n: number; PDGFRA: platelet-derived growth factor receptor A; WT: wild type.…”

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

“…Given the known heterogeneity within PDGFRA-mutant GIST, the differential immunological profile of PDGFRA D842V-mutant GIST in comparison with other PDGFRA mutants was subsequently investigated in order to better understand if the previously observed prominent immune features belong to all PDGFRA-mutant GIST or if they represent a specific peculiar fingerprint of the D842V mutant subgroup [36]. [36][37][38]. Abbreviations: GIST: gastrointestinal stromal tumors; n: number; PDGFRA: platelet-derived growth factor receptor A; WT: wild type.…”

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

“…Another unexpected but intriguing novelty of the last year is that PDGFRA-mutant GIST seem to be more immunologically active than other molecular subtypes of GIST [ 36 , 37 , 38 ].…”

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

“…In line with previous data, a recent study confirmed that tumor genotype contributes to shaping the immunogenicity of GIST [ 32 ]. In particular, in a cohort of 38 primary, untreated GIST patients, including five cases of PDGFRA-mutant GIST (two D842V mutant) and in a larger cohort of 77 GIST patients, including 15 cases of PDGFRA-mutant GIST (six D842V mutant), PDGFRA-mutant GIST presented a greater extent of immune infiltration and cytolytic activity, which were associated with increased levels of chemokines and a greater number of mutation-derived, high-affinity neoepitopes [ 38 ]. To evaluate the potential susceptibility to immunomodulatory-based treatments of the different genotypes, the immunophenoscore (IPS), a machine learning-based classifier based on the expression of HLA genes, immunomodulators, effector, and suppressor cells, capable of predicting the relative sensitivity to immune checkpoint inhibitors (ICIs), was highest in PDGFRA-mutant GIST [ 38 ].…”

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

“… Schematic figure reporting molecular findings of recent immune-profiling studies on GIST, including D842V mutant malignancies [ 36 , 37 , 38 ]. Abbreviations: GIST: gastrointestinal stromal tumors; n: number; PDGFRA: platelet-derived growth factor receptor A; WT: wild type.…”

Section: Figurementioning

confidence: 99%

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The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

Rizzo

Pantaleo

Astolfi

et al. 2021

Cancers

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The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor—avapritinib—that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.

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Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

“…Another unexpected but intriguing novelty of the last year is that PDGFRA-mutant GIST seem to be more immunologically active than other molecular subtypes of GIST [ 36 , 37 , 38 ].…”

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

Section: Immunological Identity Of D842v-mutant Gistmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

Rizzo

Pantaleo

Astolfi

et al. 2021

Cancers

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Role of ANO1 in tumors and tumor immunity

Wang

et al. 2022

J Cancer Res Clin Oncol

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Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone

et al. 2023

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AimsEpithelioid haemangioma (EH) of bone remains a highly controversial entity. Indeed, the WHO classifies EHs of soft tissues as benign tumours, whereas bone EHs are considered intermediate–locally aggressive tumours due to common multifocal presentation and local destructive growth. To gain insights into the clinical behaviour and biology of EH of bone we retrospectively analysed 42 patients treated in a single institution from 1978 to 2021.Methods and resultsMultifocal presentation was detected in 17 of 42 patients (40%) primarily as synchronous lesions. Patients were treated with curettage (57%), resection (29%) or biopsy, followed by radiotherapy or embolisation (14%). Follow‐up (minimum 24 months) was available for 38 patients, with only five local recurrences (13%) and no death of disease. To clarify whether the synchronous bone lesions in multifocal EH represent multicentric disease or clonal dissemination, four cases were profiled by RNA‐sequencing. Separate lesions from the same patient, which showed a similar transcriptional profile, expressed the same fusion transcript (involving FOS or FOSB) with identical gene breakpoints.ConclusionsThese results indicate that, in EH of bone, multifocal lesions are clonally related and therefore represent the spread of a same neoplastic clone rather than simultaneous independent tumours. This finding is in apparent contradiction with the benign clinical course of the disease, and suggests that tumour dissemination in bone EH probably reflects a phenomenon of passive spreading, with tumour cells colonising distal sites while maintaining their benign biological nature.

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Tumor genotype, location, and malignant potential shape the immunogenicity of primary untreated gastrointestinal stromal tumors

Cited by 12 publications

References 86 publications

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

Role of ANO1 in tumors and tumor immunity

Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone

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