GPC4, THE GENE OF SIMPSON-GOLABI-BEHMEL SYNDROME, IS AMPLIFIED ON EXON 9 AND REVEAL A POSSIBLE PATHOGENETIC ROLE FOR APL PROGRESSION OR RELAPSE.
(Abstract release date: 05/19/16)
EHA Library. Lo Monaco S. 06/09/16; 134534; PB1634
Dr. Silvia Lo Monaco
Contributions
Contributions
Abstract
Abstract: PB1634
Type: Publication Only
Background
Cytogenetical and molecular analysis of acute promyelocytic leukemia (APL) have improved the knowledge about the genomic mechanism at the origin of this pathology identifying t(15;17) and the fusion gene PML-RARa. New targeted therapies were introduced in treatment of APL, as all-trans retinoic acid (ATRA) and arsenic trioxide. Even though these therapies, a 10% of patients (pts) still relapse. Single Nucleotide Polymorphism (SNP) microarray can detect cytogenetic lesions mostly involving structural alterations with losses or gains of chromosomic material. These abnormalities could be predictive of response and can help define therapeutic strategies. SNP microarray can also detect copy-neutral loss of heterozygosity (CN-LOH) or Uniparental Disomy (UPD), relevant to induce oncogene duplication, tumor suppressor inhibition and epigenetic reprogramming.
Aims
To improve conventional cytogenetic analysis and identify new genomic abnormalities that underlie the pathogenesis of APL, we perform SNP array-based genotyping.
Methods
We performed SNP 6.0 and Cytoscan HD Array (Affymetrix) in 23 APL (21 de novo and 2 relapsed) and then analyzed by Nexus Copy Number (BioDiscovery, v.7.5) and R-Bioconductor. This method reveal Copy Number Alteration (CNA) and CN-LOH that standard cytogenetic analysis could not detect. Briefly, CNA were filtered for variants already annotated in Database of Genomic Variants (DGV). Furthermore, CNA less than 1 kb were removed. Significant (p<0.05) genes in which CNA events occur were summarized per patients. Moreover, commons CNV regions among patients were detected.All the pts in our cohort were treated at the hematological Institute of Bologna. Each patient was affected by newly diagnosed or relapsed APL, in accordance with WHO 2008 classification. All of them were treated with ATRA-IDA schedule of therapy.
Results
By Nexus Copy Number, we found that the relapsed pts presented more CNA than the newly diagnosis, in particular 3 out of 23 pts (a newly diagnosis and 2 relapses), showed interesting alteration on GPC4 (exon 9) and in the q26.2region of GPC3. We found that this group of 3 pts presented a minimal common region of amplification of GPC4 (chr X: 132,432,100-132,435,915) with a significant p value (p<0.05).Moreover, GPC3 q26.2 region presented significant abnormalities with more copy number gain and copy number loss, which may play a role in the pathogenesis of APL. Also UPD were found for both GPC4 (5\23 pts) and GPC3 (6\23 pts) genes, with a p value of 0.0264 for GPC4 and 0.009 for GPC3.
Conclusion
GPC4 and GPC3 are coding genes for glypicans, heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. Alteration of these genes are described as first events in the pathogenesis of Simpson-Golabi-Behmel syndrome, characterized by abnormal cellular proliferation and augmented cancer risk. Our suggestion is that these two genes may play a role in the improvement of pathogenesis and resistance of APL pts. Further studies will be necessary to confirm and validate these data in order to understand the role of these genes in APL.Aknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project
Session topic: E-poster
Keyword(s): APL, SNP
Type: Publication Only
Background
Cytogenetical and molecular analysis of acute promyelocytic leukemia (APL) have improved the knowledge about the genomic mechanism at the origin of this pathology identifying t(15;17) and the fusion gene PML-RARa. New targeted therapies were introduced in treatment of APL, as all-trans retinoic acid (ATRA) and arsenic trioxide. Even though these therapies, a 10% of patients (pts) still relapse. Single Nucleotide Polymorphism (SNP) microarray can detect cytogenetic lesions mostly involving structural alterations with losses or gains of chromosomic material. These abnormalities could be predictive of response and can help define therapeutic strategies. SNP microarray can also detect copy-neutral loss of heterozygosity (CN-LOH) or Uniparental Disomy (UPD), relevant to induce oncogene duplication, tumor suppressor inhibition and epigenetic reprogramming.
Aims
To improve conventional cytogenetic analysis and identify new genomic abnormalities that underlie the pathogenesis of APL, we perform SNP array-based genotyping.
Methods
We performed SNP 6.0 and Cytoscan HD Array (Affymetrix) in 23 APL (21 de novo and 2 relapsed) and then analyzed by Nexus Copy Number (BioDiscovery, v.7.5) and R-Bioconductor. This method reveal Copy Number Alteration (CNA) and CN-LOH that standard cytogenetic analysis could not detect. Briefly, CNA were filtered for variants already annotated in Database of Genomic Variants (DGV). Furthermore, CNA less than 1 kb were removed. Significant (p<0.05) genes in which CNA events occur were summarized per patients. Moreover, commons CNV regions among patients were detected.All the pts in our cohort were treated at the hematological Institute of Bologna. Each patient was affected by newly diagnosed or relapsed APL, in accordance with WHO 2008 classification. All of them were treated with ATRA-IDA schedule of therapy.
Results
By Nexus Copy Number, we found that the relapsed pts presented more CNA than the newly diagnosis, in particular 3 out of 23 pts (a newly diagnosis and 2 relapses), showed interesting alteration on GPC4 (exon 9) and in the q26.2region of GPC3. We found that this group of 3 pts presented a minimal common region of amplification of GPC4 (chr X: 132,432,100-132,435,915) with a significant p value (p<0.05).Moreover, GPC3 q26.2 region presented significant abnormalities with more copy number gain and copy number loss, which may play a role in the pathogenesis of APL. Also UPD were found for both GPC4 (5\23 pts) and GPC3 (6\23 pts) genes, with a p value of 0.0264 for GPC4 and 0.009 for GPC3.
Conclusion
GPC4 and GPC3 are coding genes for glypicans, heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. Alteration of these genes are described as first events in the pathogenesis of Simpson-Golabi-Behmel syndrome, characterized by abnormal cellular proliferation and augmented cancer risk. Our suggestion is that these two genes may play a role in the improvement of pathogenesis and resistance of APL pts. Further studies will be necessary to confirm and validate these data in order to understand the role of these genes in APL.Aknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project
Session topic: E-poster
Keyword(s): APL, SNP
Abstract: PB1634
Type: Publication Only
Background
Cytogenetical and molecular analysis of acute promyelocytic leukemia (APL) have improved the knowledge about the genomic mechanism at the origin of this pathology identifying t(15;17) and the fusion gene PML-RARa. New targeted therapies were introduced in treatment of APL, as all-trans retinoic acid (ATRA) and arsenic trioxide. Even though these therapies, a 10% of patients (pts) still relapse. Single Nucleotide Polymorphism (SNP) microarray can detect cytogenetic lesions mostly involving structural alterations with losses or gains of chromosomic material. These abnormalities could be predictive of response and can help define therapeutic strategies. SNP microarray can also detect copy-neutral loss of heterozygosity (CN-LOH) or Uniparental Disomy (UPD), relevant to induce oncogene duplication, tumor suppressor inhibition and epigenetic reprogramming.
Aims
To improve conventional cytogenetic analysis and identify new genomic abnormalities that underlie the pathogenesis of APL, we perform SNP array-based genotyping.
Methods
We performed SNP 6.0 and Cytoscan HD Array (Affymetrix) in 23 APL (21 de novo and 2 relapsed) and then analyzed by Nexus Copy Number (BioDiscovery, v.7.5) and R-Bioconductor. This method reveal Copy Number Alteration (CNA) and CN-LOH that standard cytogenetic analysis could not detect. Briefly, CNA were filtered for variants already annotated in Database of Genomic Variants (DGV). Furthermore, CNA less than 1 kb were removed. Significant (p<0.05) genes in which CNA events occur were summarized per patients. Moreover, commons CNV regions among patients were detected.All the pts in our cohort were treated at the hematological Institute of Bologna. Each patient was affected by newly diagnosed or relapsed APL, in accordance with WHO 2008 classification. All of them were treated with ATRA-IDA schedule of therapy.
Results
By Nexus Copy Number, we found that the relapsed pts presented more CNA than the newly diagnosis, in particular 3 out of 23 pts (a newly diagnosis and 2 relapses), showed interesting alteration on GPC4 (exon 9) and in the q26.2region of GPC3. We found that this group of 3 pts presented a minimal common region of amplification of GPC4 (chr X: 132,432,100-132,435,915) with a significant p value (p<0.05).Moreover, GPC3 q26.2 region presented significant abnormalities with more copy number gain and copy number loss, which may play a role in the pathogenesis of APL. Also UPD were found for both GPC4 (5\23 pts) and GPC3 (6\23 pts) genes, with a p value of 0.0264 for GPC4 and 0.009 for GPC3.
Conclusion
GPC4 and GPC3 are coding genes for glypicans, heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. Alteration of these genes are described as first events in the pathogenesis of Simpson-Golabi-Behmel syndrome, characterized by abnormal cellular proliferation and augmented cancer risk. Our suggestion is that these two genes may play a role in the improvement of pathogenesis and resistance of APL pts. Further studies will be necessary to confirm and validate these data in order to understand the role of these genes in APL.Aknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project
Session topic: E-poster
Keyword(s): APL, SNP
Type: Publication Only
Background
Cytogenetical and molecular analysis of acute promyelocytic leukemia (APL) have improved the knowledge about the genomic mechanism at the origin of this pathology identifying t(15;17) and the fusion gene PML-RARa. New targeted therapies were introduced in treatment of APL, as all-trans retinoic acid (ATRA) and arsenic trioxide. Even though these therapies, a 10% of patients (pts) still relapse. Single Nucleotide Polymorphism (SNP) microarray can detect cytogenetic lesions mostly involving structural alterations with losses or gains of chromosomic material. These abnormalities could be predictive of response and can help define therapeutic strategies. SNP microarray can also detect copy-neutral loss of heterozygosity (CN-LOH) or Uniparental Disomy (UPD), relevant to induce oncogene duplication, tumor suppressor inhibition and epigenetic reprogramming.
Aims
To improve conventional cytogenetic analysis and identify new genomic abnormalities that underlie the pathogenesis of APL, we perform SNP array-based genotyping.
Methods
We performed SNP 6.0 and Cytoscan HD Array (Affymetrix) in 23 APL (21 de novo and 2 relapsed) and then analyzed by Nexus Copy Number (BioDiscovery, v.7.5) and R-Bioconductor. This method reveal Copy Number Alteration (CNA) and CN-LOH that standard cytogenetic analysis could not detect. Briefly, CNA were filtered for variants already annotated in Database of Genomic Variants (DGV). Furthermore, CNA less than 1 kb were removed. Significant (p<0.05) genes in which CNA events occur were summarized per patients. Moreover, commons CNV regions among patients were detected.All the pts in our cohort were treated at the hematological Institute of Bologna. Each patient was affected by newly diagnosed or relapsed APL, in accordance with WHO 2008 classification. All of them were treated with ATRA-IDA schedule of therapy.
Results
By Nexus Copy Number, we found that the relapsed pts presented more CNA than the newly diagnosis, in particular 3 out of 23 pts (a newly diagnosis and 2 relapses), showed interesting alteration on GPC4 (exon 9) and in the q26.2region of GPC3. We found that this group of 3 pts presented a minimal common region of amplification of GPC4 (chr X: 132,432,100-132,435,915) with a significant p value (p<0.05).Moreover, GPC3 q26.2 region presented significant abnormalities with more copy number gain and copy number loss, which may play a role in the pathogenesis of APL. Also UPD were found for both GPC4 (5\23 pts) and GPC3 (6\23 pts) genes, with a p value of 0.0264 for GPC4 and 0.009 for GPC3.
Conclusion
GPC4 and GPC3 are coding genes for glypicans, heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. Alteration of these genes are described as first events in the pathogenesis of Simpson-Golabi-Behmel syndrome, characterized by abnormal cellular proliferation and augmented cancer risk. Our suggestion is that these two genes may play a role in the improvement of pathogenesis and resistance of APL pts. Further studies will be necessary to confirm and validate these data in order to understand the role of these genes in APL.Aknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project
Session topic: E-poster
Keyword(s): APL, SNP
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