Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients

// David S. Moura 1 , Rafael Ramos 2 , Antonio Fernandez-Serra 3 , Teresa Serrano 4 , Julia Cruz 5 , Ramiro Alvarez-Alegret 6 , Rosa Ortiz-Duran 7 , Luis Vicioso 8 , Maria Luisa Gomez-Dorronsoro 9 , Xavier Garcia del Muro 10 , Javier Martinez-Trufero 11 , Jordi Rubio-Casadevall 12 , Isabel Sevilla 13 , Nuria Lainez 14 , Antonio Gutierrez 15 , Cesar Serrano 16 , Maria Lopez-Alvarez 1 , Nadia Hindi 1, 17 , Miguel Taron 1 , Jose Antonio Lopez-Guerrero 3 and Javier Martin-Broto 1, 17 1 Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain 2 Pathology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain 3 Laboratory of Molecular Biology, Valencian Oncologic Institute, Valencia, Spain 4 Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain 5 Pathology Department, Valencian Oncologic Institute, Valencia, Spain 6 Pathology Department, Miguel Servet University Hospital, Zaragoza, Spain 7 Pathology Department, Josep Trueta University Hospital, Girona, Spain 8 Pathology Department, Virgen de la Victoria University Hospital, Malaga, Spain 9 Pathology Department, Hospital Complex of Navarra, Pamplona, Spain 10 Medical Oncology Department, Institut Catala d'Oncologia, IDIBELL, Universitat de Barcelona, Barcelona, Spain 11 Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain 12 Medical Oncology Department, Catalan Oncologic Institute, Josep Trueta University Hospital, Girona, Spain 13 Medical Oncology Department, Virgen de la Victoria University Hospital, Malaga, Spain 14 Medical Oncology Department, Hospital Complex of Navarra, Pamplona, Spain 15 Hematology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain 16 Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain 17 Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain Correspondence to: Javier Martin-Broto, email: jmartin@mustbesevilla.org Jose Antonio Lopez-Guerrero, email: jalopez@fivo.org Keywords: KNGL; miRNA221/222 cluster; KIT; DOG1; IGF1R Received: July 27, 2017      Accepted: February 28, 2018      Published: April 03, 2018 ABSTRACT Introduction: There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT , PDGFRA , DOG1 , IGF1R , MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT , DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT , DOG1 and PDGFRA . Group II had a significant worse OS ( p = 0.013) in all the series, and showed a tendency for worse OS ( p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST ( p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 ( p = 0.028) or MIR222 ( p = 0.014). Conclusions: We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.