Site‐independent prognostic value of chromosome 9q loss in primary gastrointestinal stromal tumours

Abstract

Although the significance of tumour site for estimating malignant potential in gastrointestinal stromal tumours (GISTs) has recently been recognized, site-specific genetic patterns have not to date been defined. This study examined 52 c-kit-positive primary GISTs (with a mean follow-up of 42.3 months in 51 cases) from three different locations (35 gastric, 12 small intestinal, and five colorectal) using comparative genomic hybridization (CGH). In general, tumour site correlated with key prognostic factors, including tumour size, mitotic rate, proliferative activity, and probable malignant potential. Furthermore, several DNA copy number changes showed a site-dependent pattern. These included losses at 14q (gastric 83%, intestinal 35%; p = 0.001), losses at 22q (gastric 46%, intestinal 82%; p = 0.02), losses at 1p (gastric 23%, intestinal 88%; p = 1 x 10(-5)), losses at 15q (gastric 14%, intestinal 59%; p = 0.002), losses at 9q (gastric 14%, intestinal 53%; p = 0.006), and gains at 5p (gastric 11%, intestinal 53%; p = 0.002). These data demonstrate strong site-dependent genetic heterogeneity in GISTs that may form a basis for subclassification. Prognostic evaluation of DNA copy number changes identified losses at 9q as a site-independent prognostic marker associated with shorter disease-free survival (p = 0.03) and overall survival (p = 0.002). Furthermore, 9q loss also appeared to carry prognostic value in predicting overall survival for patients with advanced or progressive GISTs (p = 0.003).

Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors

“…Previous studies using conventional CGH and/or array-based genomic profiling indicated that loss of chromosome 9, especially 9p, is a specific indicator of unfavorable outcomes in GISTs (16)(17)(18). We corroborated this association by using ultrahigh-resolution aCGH, showing a striking predilection of chromosome 9 deletions, mostly involving both arms, in high-risk GISTs (70%).…”

“…We corroborated this association by using ultrahigh-resolution aCGH, showing a striking predilection of chromosome 9 deletions, mostly involving both arms, in high-risk GISTs (70%). Compared with previous series (15)(16)(17)(18)(19), the higher prevalence of 9p losses in high-risk GISTs may be attributable to better resolution of the current aCGH platform in detecting subtle interstitial deletions. Specifically, GISTs with chromosome 9 losses almost all involved the probe sets within 9p21.3 where p16 INK4A , the leading TSG of CDKN2A/2B loci, was recurrently inactivated in aggressive GISTs by various mechanisms, including the most common homozygous deletion (20,38).…”

“…observed in advanced GISTs (15)(16)(17)(18)(19)(20). To pinpoint potential TSGs associated with tumor progression in chromosome 9, we used oligonucleotide-based array comparative genomic hybridization (aCGH) with ultrahigh-resolution for profiling copy number alterations in 22 GISTs.…”

Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms

“…10 Some of these studies have implicated the 9q32-33 region as the prevailing target for deletion, suggesting that this region harbors an important tumor suppressor gene for lymphoproliferative cancers. The same region is lost in several other types of human cancers 11 with particularly high frequencies reported for transitional cell carcinomas of the bladder. 12 Fine mapping analysis in bladder cancer led to the identification of a putative tumor suppressor gene at 9q33.1, which has been designated as DBC1 (deleted in bladder cancer 1).…”

Gastrointestinal Stromal Tumours: A Contemporary Review on Pathogenesis, Morphology and Prognosis

“…Cytogenetic studies have reported correlations between the acquisition of additional chromosomal changes and aggressive behaviour such as gains at 5p and 20q and losses at chromosomes 1p, 9q and 9p. Gains at 8q and 17q have been detected in metastatic GISTs far more frequently than in primary tumours (Breiner et al, 2000;Debiec-Rychter et al, 2001;Derre et al, 2001;Gunawan et al, 2004;Kim et al, 2000;Miettinen et al, 2002a;O'Leary et al, 1999). Therefore, these chromosomal aberrations appear to be secondary events and may play an important role in tumour progression (Heinrich et al, 2003a) ( Figure 5).…”