Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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.
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. The two splice-site mutations cases 7 and 59 destroyed invariant splicing motifs, creating inactive MAX transcripts with loss of exon 3 case 7 or retention of intron 4 case 59 , as confirmed by reverse transcriptaseโPCR, andโfor case 7โalso confirmed by genome RNA sequencing Supplementary Fig.
Multiple anatomically distinct specimens were studied in five patients pts with MAX -mutant GISTs and all had identical mutations, as shown by comparisons of primary GIST and subsequent metastases in two pts, and by comparisons of multiple metastases twoโten metastases analysed per pt in three pts Supplementary Data 2 and Supplementary Fig. Inactivating MAX mutations were intragenic homozygous deletions blue lines indicate deleted exons and hemizygous mononucleotide alterations.
Among the overall study group of 76 GISTs, the GIST primary site was known for 71 pts, whereas primary site could not be determined in the remaining 5 pts who presented with disseminated intra-abdominal disease. The cases, from left to right in a are 21, 22, 32, 3, 39, 58 and 53, and in b are 73, 68, 71, 74, 76, 75 and 7. Residual MAX expression in MAX -mutant cases 53, 73, 68, 76 and 7 results from non-neoplastic cells fibroblasts, endothelial cells and inflammatory cells and from admixed precursor GIST cells that had not yet acquired the MAX mutations.
Positive internal controls for MAX expression in all cases are scattered inflammatory cells and fibrovascular cells, andโin case 51โa lymphoid aggregate at the upper left. CDKN2A ranked in the top 0.
