An oncogenetic tree model in gastrointestinal stromal tumours (GISTs) identifies different pathways of cytogenetic evolution with prognostic implications

Abstract

To model the cytogenetic evolution in gastrointestinal stromal tumour (GIST), an oncogenetic tree model was reconstructed using comparative genomic hybridization data from 203 primary GISTs (116 gastric and 87 intestinal GISTs, including 151 newly analysed cases), with follow-up available in 173 cases (mean 40 months; maximum 133 months). The oncogenetic tree model identified three major cytogenetic pathways: one initiated by -14q, one by -1p, and another by -22q. The -14q pathway mainly characterized gastric tumours with predominantly stable karyotypes and more favourable clinical course. On the other hand, the -1p pathway was more characteristic of intestinal GISTs, with an increased capacity for cytogenetic complexity and more aggressive clinical course. Loss of 22q, more closely associated with -1p than -14q, appeared to initiate the critical transition to an unfavourable cytogenetic subpathway. This -22q pathway included accumulation of +8q, -9p, and -9q, which could all predict disease-free survival in addition to tumour site. Thus, insights into the cytogenetic evolution obtained from oncogenetic tree models may eventually help to gain a better understanding of the heterogeneous site-dependent biological behaviour of GISTs.

Gastrointestinal stromal tumors: what do we know now?

“…37,43,85,86,89,91 Losses on chromosomes 1p, 9p, 11p, and 17p are successively less common than 14q and 22q losses, but are more significantly associated with malignancy ( Figure 4). 37,43,85,89,[91][92][93][94] Losses on chromosomes 10, 13q, and 15q have also been reported in GISTs. 43,91 Gains on chromosomes 8q (including MYC), 3q (including SMARCA3), and 17q are associated with metastatic behavior.…”

“…37,43,85,89,[91][92][93][94] Losses on chromosomes 10, 13q, and 15q have also been reported in GISTs. 43,91 Gains on chromosomes 8q (including MYC), 3q (including SMARCA3), and 17q are associated with metastatic behavior. 86,95 In a recent array-based analysis of gene copy number in 42 GISTs (23 with recurrence or metastasis), the tumors were separated into four groups reflecting their accumulated chromosomal changes.…”

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

“…This suggests that these genetics aberrations may be important in both early tumor development and progression. [8][9][10][11][12][13][14][15][16][17][18][19][20] Gunawan et al 8 have recently proposed an oncogenetic tree model identifying three major cytogenetic pathways in 203 primary GISTs: one initiated by À14q, one by À1p and another by À22q, with different biologic and clinical behavior. GISTs involving the À14q pathway were predominantly gastric tumors with stable karyotype and more favorable clinical course.…”

“…These chromosomal losses may represent an underlying pathogenetic event resulting in the inactivation or haploinsufficiency of tumor suppressor genes. [8][9][10][11][12][13][14][15][16][17][18][19][20] However, the biologic significance of these genetic alterations, as well as their clinical implications, remains unknown. To address this issue, we performed an integrative analysis of gene expression profiling and high-resolution genomic copy number in 25 GIST samples to investigate the relationship between karyotype and gene expression profile, and to identify new haploinsufficient tumor suppressor genes involved in GIST pathogenesis and tumor progression.…”

Reverse‐phase protein arrays for application‐orientated cancer research

“…Tibes et al [24] reported increased levels of phosho-extracellular signal regulated kinase 1/2 and phospho-AKT (Thr-308) but also of phospho-mTOR (Ser-2448) in acute myeloid leukemia. Another study showed that in 70% of gastrointestinal stromal tumors (GISTs), a loss of chromosome 14q encoding AKT1 is observed [28]. Subsequent qRT-PCR and RPPAbased experiments revealed a reduced expression of AKT1 protein in line with the heterozygous loss but a slightly increased abundance of phospho-AKT ( Fig.…”