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Revised supplementary Figure 1 from Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

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posted on 2023-04-03, 17:23 authored by Maria A. Pantaleo, Milena Urbini, Valentina Indio, Gloria Ravegnini, Margherita Nannini, Matilde De Luca, Giuseppe Tarantino, Sabrina Angelini, Alessandro Gronchi, Bruno Vincenzi, Giovanni Grignani, Chiara Colombo, Elena Fumagalli, Lidia Gatto, Maristella Saponara, Manuela Ianni, Paola Paterini, Donatella Santini, M. Giulia Pirini, Claudio Ceccarelli, Annalisa Altimari, Elisa Gruppioni, Salvatore L. Renne, Paola Collini, Silvia Stacchiotti, Giovanni Brandi, Paolo G. Casali, Antonio D. Pinna, Annalisa Astolfi, Guido Biasco

Graphical view of copy number analysis. Copy number alterations detected on the chromosomes most frequently deleted in GIST (chr1, chr14 and chr22). For each patient a green bar indicates an heterozygously deleted region and a red bar indicates a gain of one copy.

Funding

Italian Association for Cancer Research AIRC

Fondazione Isabella Seragnoli, Bologna, Italy

History

ARTICLE ABSTRACT

Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway 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 with SDH and KIT/PDGFRA-mutant 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 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and 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 upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share 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 and should promote the development of specific therapeutic approaches. Mol Cancer Res; 15(5); 553–62. ©2017 AACR.