Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in Quadruple WT GIST

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 CeccarelliAnnalisa Altimari, Elisa Gruppioni, Salvatore L. Renne, Paola Collini, Silvia Stacchiotti, Giovanni Brandi, Paolo G. Casali, Antonio D. Pinna, Annalisa Astolfi, Guido Biasco

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)553-562
Number of pages10
JournalMolecular Cancer Research
Volume15
Issue number5
DOIs
Publication statusPublished - May 1 2017

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Multiple Endocrine Neoplasia Type 1
Gastrointestinal Stromal Tumors
Genome
Mutation
Exome
Succinate Dehydrogenase
MicroRNAs
Genes
Neuroendocrine Tumors
Transcriptome
Up-Regulation
Phenotype
Gene Expression
Messenger RNA
DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in Quadruple WT GIST. / Pantaleo, Maria A.; Urbini, Milena; Indio, Valentina; Ravegnini, Gloria; Nannini, Margherita; De Luca, Matilde; Tarantino, Giuseppe; Angelini, Sabrina; Gronchi, Alessandro; Vincenzi, Bruno; Grignani, Giovanni; Colombo, Chiara; Fumagalli, Elena; Gatto, Lidia; Saponara, Maristella; Ianni, Manuela; Paterini, Paola; Santini, Donatella; Pirini, M. Giulia; Ceccarelli, Claudio; Altimari, Annalisa; Gruppioni, Elisa; Renne, Salvatore L.; Collini, Paola; Stacchiotti, Silvia; Brandi, Giovanni; Casali, Paolo G.; Pinna, Antonio D.; Astolfi, Annalisa; Biasco, Guido.

In: Molecular Cancer Research, Vol. 15, No. 5, 01.05.2017, p. 553-562.

Research output: Contribution to journalArticle

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 & Biasco, G 2017, 'Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in Quadruple WT GIST', Molecular Cancer Research, vol. 15, no. 5, pp. 553-562. https://doi.org/10.1158/1541-7786.MCR-16-0376
Pantaleo, Maria A. ; Urbini, Milena ; Indio, Valentina ; Ravegnini, Gloria ; Nannini, Margherita ; De Luca, Matilde ; Tarantino, Giuseppe ; Angelini, Sabrina ; Gronchi, Alessandro ; Vincenzi, Bruno ; Grignani, Giovanni ; Colombo, Chiara ; Fumagalli, Elena ; Gatto, Lidia ; Saponara, Maristella ; Ianni, Manuela ; Paterini, Paola ; Santini, Donatella ; Pirini, M. Giulia ; Ceccarelli, Claudio ; Altimari, Annalisa ; Gruppioni, Elisa ; Renne, Salvatore L. ; Collini, Paola ; Stacchiotti, Silvia ; Brandi, Giovanni ; Casali, Paolo G. ; Pinna, Antonio D. ; Astolfi, Annalisa ; Biasco, Guido. / Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in Quadruple WT GIST. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 5. pp. 553-562.
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AU - Pantaleo, Maria A.

AU - Urbini, Milena

AU - Indio, Valentina

AU - Ravegnini, Gloria

AU - Nannini, Margherita

AU - De Luca, Matilde

AU - Tarantino, Giuseppe

AU - Angelini, Sabrina

AU - Gronchi, Alessandro

AU - Vincenzi, Bruno

AU - Grignani, Giovanni

AU - Colombo, Chiara

AU - Fumagalli, Elena

AU - Gatto, Lidia

AU - Saponara, Maristella

AU - Ianni, Manuela

AU - Paterini, Paola

AU - Santini, Donatella

AU - Pirini, M. Giulia

AU - Ceccarelli, Claudio

AU - Altimari, Annalisa

AU - Gruppioni, Elisa

AU - Renne, Salvatore L.

AU - Collini, Paola

AU - Stacchiotti, Silvia

AU - Brandi, Giovanni

AU - Casali, Paolo G.

AU - Pinna, Antonio D.

AU - Astolfi, Annalisa

AU - Biasco, Guido

PY - 2017/5/1

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