MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation
Journal
Nature Communications
Journal Volume
8
Date Issued
2017
Abstract
KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ?70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs. ? 2017 The Author(s).
SDGs
Other Subjects
Max protein; protein p16; basic helix loop helix leucine zipper transcription factor; cyclin dependent kinase inhibitor 2A; MAX protein, human; neurofibromin; P16 protein, human; platelet derived growth factor alpha receptor; stem cell factor receptor; succinate dehydrogenase; cells and cell components; chromosome; gene expression; mutation; protein; tumor; Article; cell cycle; cell proliferation; chromosome 14q; controlled study; gastrointestinal stromal tumor; gene deletion; gene inactivation; gene mutation; gene sequence; genomics; human; human cell; protein expression; tumor growth; cell proliferation; chromosome 14; chromosome deletion; disease exacerbation; dna mutational analysis; female; gastrointestinal stromal tumor; gastrointestinal tumor; gene silencing; genetics; loss of function mutation; male; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Cycle; Cell Proliferation; Chromosome Deletion; Chromosomes, Human, Pair 14; Cyclin-Dependent Kinase Inhibitor p16; Disease Progression; DNA Mutational Analysis; Female; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Silencing; Humans; Loss of Function Mutation; Male; Neurofibromin 1; Proto-Oncogene Proteins c-kit; Receptor, Platelet-Derived Growth Factor alpha; Succinate Dehydrogenase
Type
journal article