The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST)

Abstract

Recent advances in molecular biology have revolutionized the concept of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumors (GIST) than the past. Indeed, from being defined as GIST without KIT or PDGFRA mutations, we are now faced with the opposite scenario, where KIT/PDGFRA WT GIST are “positively” defined according to their specific molecular alterations. In particular, if until recently KIT/PDGFRA GIST without abnormalities of KIT, PDGFRA, SDH, and the RAS signaling pathway were referred as quadruple WT GIST, today also this small subset of GIST is emerging out as a group of heterogeneous distinct entities with multiple different molecular alterations. Therefore, given this still growing and rapidly evolving scenario, the progressive molecular fragmentation may inevitably lead over the time to the disappearance of KIT/PDGFRA WT GIST, destined to be singularly defined by their molecular fingerprint.

Targeted Deep Sequencing Uncovers Cryptic KIT Mutations in KIT/PDGFRA/SDH/RAS-P Wild-Type GIST

“…Quadruple-WT GIST represent an undefined and heterogeneous category of tumors (15,27), that inevitably poorly respond to standard treatments, represented by TKI, due to the lack of the target oncogenic alteration. The detection of a significant fraction of this subgroup as carrier of actionable KIT mutations not only advocates the routine implementation of next generation sequencing approaches in the current molecular diagnostic protocols, but also opens new and effective therapeutic strategies for these patients, that are actually devoid of active pharmacological opportunities.…”

Genomic-guided precision therapy for soft tissue sarcoma

“…In a phase II trial with Simon two-stage design, no objective response was observed in the first nine patients, and vandetanib was thus considered inactive 37. In wild-type GIST patients with competent SDH, 4%–13% carried the BRAF V600E mutation 38. One case report described a response to the BRAF inhibitor in a patient with BRAF V600E-mutated GIST 39…”

Living Donor Liver Transplantation for Imatinib‐Resistant Gastrointestinal Stromal Tumor Liver Metastases: A New Therapeutic Option in Transplant Oncology

“…More than 10 years have passed since the GIST community defined a new molecular profile that inevitably leads, over time, to the disappearance of KIT/ PDGFRA WT GIST that was emerging as a group of heterogeneous distinct entities with multiple molecular alterations. (2,3) KIT/PDGFRA WT GISTs include at least 5 main subgroups: Succinate deyhidrogenase (SDH)-deficient GISTs mainly characterized by A, B, C, and D gene mutations; RAS pathway-mutated GISTs, with mutations in neurofibromatosis 1, BRAF or K-RAS; fibroblast growth factor receptor (FGFR) pathway-deregulated GISTs; Neutrophic tropomyosin receptor kinase (NTRK)-positive GISTs; and the pan-WT GIST/all negative WT GIST.…”