Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors

doi:10.1053/hupa.2002.32216

Human Pathology

Volume 33, Issue 3, March 2002, Pages 316-321

https://doi.org/10.1053/hupa.2002.32216 Get rights and content

Abstract

We report cytogenetic findings in 19 c-Kit–positive gastrointestinal stromal tumors (GISTs) that represent a heterogenous group of mesenchymal neoplasms with respect to site, histology, and biologic behavior. All of the GISTs (5 low-risk, 11 high-risk, 3 recurrences) displayed clonal chromosomal aberrations; 15 were hypo- to near-diploid, and 4 were near-triploid and hypotetraploid. The most common abnormalities were loss of chromosomes 14 and/or 22, demonstrated in 14 GISTs irrespective of site or predominant phenotype. Ten cases (2 low-risk, 5 high-risk, 3 recurrences) were characterized by loss of both chromosomes 14 and 22, 2 cases (1 low-risk, 1 high- risk), by loss of chromosome 14; and 2 high-risk cases, by loss of chromosome 22. Additional chromosomal aberrations occurred preferentially in high-risk and recurrent GISTs, including loss of 9p and 1p in 8 cases each, loss of 15 in 6 cases, loss of 3p in 5 cases, loss of 13q and 10q in 4 cases each, loss of 19 in 3 cases, and complete or partial gains of chromosomes 5 and 4 in 2 cases each. More significantly, 5 of 6 patients with clinically aggressive GISTs, including 2 recurrences and 3 metastasing GISTs, were additionally characterized by loss of 9p; four of these had additional loss of chromosomes 1p and 15. The presented results herein indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of site or differentiation, whereas malignant transformation and progression of GISTs appear to be associated with an increasing incidence of additional secondary aberrations. HUM PATHOL 33:316-321. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Materials and methods

For routine histomorphologic analysis, 19 GISTs were sampled and processed for histomorphologic examination according to standard procedures. Descriptive histomorphologic criteria included cell shape, cellular arrangement, cellularity, and degree of nuclear pleomorphism. Primary GISTs were classified as low- or high-risk tumors for their estimated potential for aggressive clinical behavior as suggested by Franquemont.⁶ Immunohistochemical analysis was performed, applying a panel of antibodies

Results

The clinicopathological data of 19 patients with GIST, including 16 primary tumors and 3 local recurrences, are summarized in Table 1.Thirteen GISTs were located in the wall of the stomach (cases 1 through 12 and 17), 1 GIST was in the duodenum (case 15), and 1 in the rectum (case 13), and 4 (cases 14, 16, 18, and 19) were intra-abdominal tumors. The patient age at the time of diagnosis ranged from 39 to 81 years (median age 62.6 years). Clinical symptoms included abdominal pain,

Discussion

On the basis of a series of 19 clinically and morphologically characterized GISTs, the possible value of chromosomal aberrations as genetic markers of tumor progression and tumor behavior were investigated. Existing cytogenetic literature regarding c-Kit (CD117)-positive GISTs is limited.2, 7, 9 Review of our data and the results of these earlier studies indicate that certain chromosomal aberrations are common to GISTs irrespective of site, differentiation and benign or malignant behavior.

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Loss of SFRP1 expression is a key progression event in gastrointestinal stromal tumor pathogenesis
2021, Human Pathology
Citation Excerpt :
When microGISTs do occasionally succeed in progression to larger clinical GISTs, the clonal evolution results from accumulation of cytogenetic abnormalities in distinct profiles. The early changes usually include monosomy 14, monosomy 22, and 1p deletion [7–10]. This is accompanied by MYC-associated factor X (MAX) gene inactivating mutation [5] followed by 9p deletion, targeting the tumor suppressor gene CDKN2A, which encodes p16 and p14 proteins, and which appears to be a crucial factor in GIST progression [8–11].
The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis, and gene expression profiling were carried out, followed by in silico analyses, cell line study, and immunohistochemical validation. Using gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p = 0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in low-grade GISTs (p < 0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p < 0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss.
Personalized medicine in gastrointestinal stromal tumors
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Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal stromal tumors
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Citation Excerpt :
The lower rate of these changes in PDGFRA- compared with KIT-mutated GISTs reflects the overall nonaggressive behavior of the tumors in our study. We also repeatedly found an association between −9p, which harbors CDKN2A/2B encoding for 3 tumor suppressor genes, and malignant behavior in GISTs [17,20,22,23,29]. Regarding PDGFRA-mutated GISTs, we here detected a statistically significant association of −9p and of −22q with intermediate/high-risk tumors, which generally correlated with our previous findings in GISTs [17,20,23,29].
Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor receptor α (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series. We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT-mutated GISTs. PDGFRA exon 18 mutations (91% of cases) and exon 12 mutations (9% of cases) correlated significantly with gastric and intestinal sites, respectively. The most common aberrations were identical to those found in KIT-mutated GISTs, with −14q in 70%, −1p in 28%, and −22q in 17% of cases. Overall, there were significantly fewer chromosomal aberrations compared with KIT-mutated GISTs, with a mean of 2.8 (0.6 gains, 2.1 losses) aberrations per tumor. There was a statistically significant association of more than 5 chromosomal imbalances with intermediate/high-risk categories. Regarding specific chromosomal aberrations, −9p, −13q, and −22q correlated with intermediate/high risk, and −1p and +8q with poorer survival, although progression occurred in only 2 cases. Altogether, PDGFRA-mutated GISTs display the same chromosomal aberrations as KIT-mutated GISTs, although they have a lower degree of chromosomal instability in line with their generally favorable outcome.
Deletions of chromosome 1p and 15q are associated with aggressiveness of gastrointestinal stromal tumors
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Site-dependent profiles of chromosome imbalances (CIs) have been reported in gastrointestinal stromal tumors (GISTs). However, the role of specific CIs in association with metastasis is not clear.
Thirteen resected liver metastatic GISTs, including seven from the stomach and six from the small intestine, were analyzed using comparative genomic hybridization (CGH). The CIs associated with metastatic risk were assessed by comparing them with those identified in our previous study of 25 primary GISTs, including 14 from the stomach and 11 from the small intestine.
Synchronous detection of liver metastasis was found more often in patients with intestinal than gastric GIST (5/6 vs. 2/7, p = 0.048). When compared with the primary tumors, the CI profile of liver metastases was similar in the intestinal group, but became more complex in the gastric group. Deletions of chromosomes 1p and 15q were very common (> 80%) in primary and metastatic tumors of the intestinal group, and exhibited a trend towards increase in the metastatic tumors of the gastric group. Both groups had a doubling in the frequency of 22q deletion in the liver metastases, which was not significantly different. Other CIs, including 9p deletion, increased significantly in the liver metastases of the gastric group, but not in the intestinal group.
Our results, together with clinical findings, indicated a CGH profile associated with the intrinsic aggressiveness of the GISTs. Deletion of 1p and 15q play a critical role in the acquisition of aggressiveness during early GIST development.
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^*: Address correspondence and reprint requests to Bastian Gunawan, MD, Department of Pathology, Georg-August-University Hospital, Robert-Koch-Str. 40, D-37075 Göttingen, Germany.

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Original ContributionsBiological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors*

Abstract

Section snippets

Materials and methods

Results

Discussion

Hum Pathol

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Hum Pathol

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Gain-of-function mutations of c-Kit in human gastrointestinal stromal tumors

Science

Gastrointestinal pacemaker cell tumor (GIPACT): Gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal

Am J Pathol

Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors

Am J Surg Pathol

Original Contributions
Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors*