Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients
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David S. Moura1, Rafael Ramos2, Antonio Fernandez-Serra3, Teresa Serrano4, Julia Cruz5, Ramiro Alvarez-Alegret6, Rosa Ortiz-Duran7, Luis Vicioso8, Maria Luisa Gomez-Dorronsoro9, Xavier Garcia del Muro10, Javier Martinez-Trufero11, Jordi Rubio-Casadevall12, Isabel Sevilla13, Nuria Lainez14, Antonio Gutierrez15, Cesar Serrano16, Maria Lopez-Alvarez1, Nadia Hindi1,17, Miguel Taron1, José Antonio López-Guerrero3 and Javier Martin-Broto1,17
1Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain
2Pathology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain
3Laboratory of Molecular Biology, Valencian Oncologic Institute, Valencia, Spain
4Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
5Pathology Department, Valencian Oncologic Institute, Valencia, Spain
6Pathology Department, Miguel Servet University Hospital, Zaragoza, Spain
7Pathology Department, Josep Trueta University Hospital, Girona, Spain
8Pathology Department, Virgen de la Victoria University Hospital, Malaga, Spain
9Pathology Department, Hospital Complex of Navarra, Pamplona, Spain
10Medical Oncology Department, Institut Català d'Oncologia, IDIBELL, Universitat de Barcelona, Barcelona, Spain
11Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain
12Medical Oncology Department, Catalan Oncologic Institute, Josep Trueta University Hospital, Girona, Spain
13Medical Oncology Department, Virgen de la Victoria University Hospital, Malaga, Spain
14Medical Oncology Department, Hospital Complex of Navarra, Pamplona, Spain
15Hematology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain
16Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
17Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain
Javier Martin-Broto, email: [email protected]
José Antonio López-Guerrero, email: [email protected]
Keywords: KNGL; miRNA221/222 cluster; KIT; DOG1; IGF1R
Received: July 27, 2017 Accepted: February 28, 2018 Published: April 03, 2018
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.
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