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Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors.

Silva M, Veiga I, Ribeiro FR, Vieira J, Pinto C, Pinheiro M, Mesquita B, Santos C, Soares M, Dinis J, Santos L, Lopes P, Afonso M, Lopes C, Teixeira MR - BMC Med (2010)

Bottom Line: Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment.Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.

ABSTRACT

Background: Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.

Methods: In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.

Results: We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with KIT mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.

Conclusions: In addition to KIT/PDGFRA mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.

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Related in: MedlinePlus

Copy number profile of patients diagnosed with GIST. Gains and losses of genetic material are depicted along all chromosomes (X axis).
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Figure 2: Copy number profile of patients diagnosed with GIST. Gains and losses of genetic material are depicted along all chromosomes (X axis).

Mentions: Out of the 29 GIST submitted to whole-genome screening, 25 (86%) displayed copy number changes (Figure 2, Additional file 2). Most abnormal samples displayed non-complex profiles, with a median of three aberrations per tumor (ranging from one to 28 changes), and losses were 1.5 times more frequent than gains. It is noteworthy that complete or partial loss of 14q was seen in 22 samples (88%), being the sole copy number change in four patients. Other frequent changes included losses at 22q (44%), 1p (44%), and 15q (36%) and gains at 1q (16%) and 12q (20%). All 25 cytogenetically abnormal GIST presented at least one of the losses 1p, 14q, or 22q.


Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors.

Silva M, Veiga I, Ribeiro FR, Vieira J, Pinto C, Pinheiro M, Mesquita B, Santos C, Soares M, Dinis J, Santos L, Lopes P, Afonso M, Lopes C, Teixeira MR - BMC Med (2010)

Copy number profile of patients diagnosed with GIST. Gains and losses of genetic material are depicted along all chromosomes (X axis).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2876987&req=5

Figure 2: Copy number profile of patients diagnosed with GIST. Gains and losses of genetic material are depicted along all chromosomes (X axis).
Mentions: Out of the 29 GIST submitted to whole-genome screening, 25 (86%) displayed copy number changes (Figure 2, Additional file 2). Most abnormal samples displayed non-complex profiles, with a median of three aberrations per tumor (ranging from one to 28 changes), and losses were 1.5 times more frequent than gains. It is noteworthy that complete or partial loss of 14q was seen in 22 samples (88%), being the sole copy number change in four patients. Other frequent changes included losses at 22q (44%), 1p (44%), and 15q (36%) and gains at 1q (16%) and 12q (20%). All 25 cytogenetically abnormal GIST presented at least one of the losses 1p, 14q, or 22q.

Bottom Line: Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment.Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.

ABSTRACT

Background: Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.

Methods: In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.

Results: We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with KIT mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.

Conclusions: In addition to KIT/PDGFRA mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.

Show MeSH
Related in: MedlinePlus