GRCh38 · COSMIC v98


This section shows a summary for the selected study (COSU identifier) or publication (COSP identifier). Studies may have been performed by the Sanger Institute Cancer Genome Project, or imported from the ICGC/TCGA. You can see more information on the help pages.

Genome-wide Analyses Identifies MEN1 and MAX Mutations and a Neuroendocrine-like Molecular Heterogeneity in Quadruple WT GIST.
Paper ID
Pantaleo MA, Urbini M, Indio V, Ravegnini G, Nannini M, De Luca M, Tarantino G, Angelini S, Gronchi A, Vincenzi B, Grignani G, Colombo C, Fumagalli E, Gatto L, Saponara M, Ianni M, Paterini P, Santini D, Pirini MG, Ceccarelli C, Altimari A, Gruppioni E, Renne SL, Collini P, Stacchiotti S, Brandi G, Casali PG, Pinna AD, Astolfi A and Biasco G
Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital
Molecular cancer research : MCR, 2017
ISSN: 1557-3125
PMID: 28130400 (view at PubMed or Europe PMC)
Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathways mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for Whole Exome Sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from Whole Transcriptome Sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared to SDH and KIT/PDGFRAmutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4 and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1, CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and up-regulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they share also the great variability in oncogenic driver genes.Implications: This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors than to GIST and should promote the development of specific therapeutic approaches.
Paper Status