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.
Highlights
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
Activating mutations of the receptor tyrosine kinases KIT1 or PDGFRA2 are initiating or early events in most gastrointestinal stromal tumours (GISTs) and are present in micro-GISTs, which are asymptomatic subcentimetre GIST lesions found in one-third of the general population[3]
We show that 14q deletions target the MAX transcriptional regulator gene in early GISTs of various molecular origins (KIT-mutant, PDGFRA-mutant or NF1-mutant)
Summary
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. Genetic progression from micro-GIST to malignant GIST results from stepwise accumulation of deletions in chromosome arms 14q, 22q, 1p and 15q, together with cell cycle dysregulating events and dystrophin inactivation[4,5,6,7,8]. These highly recurrent chromosomal deletions implicate losses of yet-unidentified tumour suppressor mechanisms in GIST progression. We show that 14q deletions target the MAX transcriptional regulator gene in early GISTs of various molecular origins (KIT-mutant, PDGFRA-mutant or NF1-mutant) These MAX genomic-inactivating mutations are driver events, enabling GIST progression by loss of MAX expression, and consequent p16 silencing and cell cycle dysregulation
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