Pan-Cancer Analysis of Expression, Mutation and Copy Number Variation of Alternative Splicing Regulator Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) Family and Their Prognostic Potential

2020 ◽  
Author(s):  
Hao Li ◽  
Jingwei Liu ◽  
Shixuan Shen ◽  
Di Dai ◽  
Shitong Cheng ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Copy Number Variation ◽  
Copy Number ◽  
Number Variation ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Splicing Regulator ◽  
Pan Cancer

scholarly journals Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng Zhang ◽  
Si-Cong Ma ◽  
Jia-Le Tan ◽  
Jian Wang ◽  
Xue Bai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Homologous Recombination Deficiency ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

BackgroundHomologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).MethodsGenome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and >10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.ResultsAt subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p < 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.ConclusionsThe CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

Post Transplant Allogeneic Antibody Responses Form against Annexin 8

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4605-4605
Author(s):  
George L. Chen ◽  
Nilou Arden ◽  
David Miklos
Keyword(s):  
Alternative Splicing ◽  
Copy Number Variation ◽  
Copy Number ◽  
Hematopoietic Cell Transplantation ◽  
Antibody Responses ◽  
Common Variant ◽  
Post Transplant ◽  
Graft Versus Leukemia ◽  
Number Variation ◽  
The Common

Abstract Allogeneic hematopoietic cell transplantation can cure hematologic malignancies through graft versus leukemia effects but are limited by graft versus host disease. Antibodies against human Y chromosome antigens are associated with graft versus host disease and we hypothesized that antibodies could conversely be associated with post transplant graft versus leukemia effects. We identified an index male patient with chronic lymphocytic leukemia who received a female PBSC graft following reduced intensity conditioning allogeneic hematopoietic cell transplantation. This F→M had developed allogeneic antibodies against H-Y antigen UTY. We hypothesized allogeneic antibodies develop against autosomal minor histocompatibility antigens and could be identified as targets of allo-antibodies. Protein microarrays (Invitrogen Protoarray) featuring 8000 baculovirus expressed human proteins with N-terminal GST fusions were screened with plasma samples from the index patient and antibodies binding to potential graft versus leukemia antigens were detected with fluorescently tagged secondary antibodies. We compared post-transplant with pre-transplant and donor plasma fluorescent intensities and identified new post transplant antibody responses against annexin 8 which were not present prior to transplant or in the donor. Our finding of new antibody responses against annexin 8 was confirmed by Western blot against E.coli expressed affinity purified recombinant V5-His6 tagged annexin 8. Annexin 8 is a membrane associated protein postulated to play a role in cellular proliferation. Recent genomic analyses have identified three loci coding for three separate annexin 8 genes clustered on chromosome 10 in a region of high frequency copy number variation (CNV). In addition, the annexin 8 mRNA transcript undergoes alternative splicing with one variant being identified from a choriocarcinoma cell line. Both CNV and alternative splicing may result in immunologic disparities between donor and recipient inducing alloimmunity.. Therefore, we tested these possibilities by synthesizing recombinant V5-His6 annexin 8 proteins corresponding to the three possible isoforms and using them in an ELISA to screen 187 patients with a variety of malignancies for post-allogeneic transplant antibodies. The recombinant proteins included the alternative splice variant from choriocarcinoma which differed from the common variant by the insertion of a 38 amino acid sequence after the second exon and the deletion of two 57 and 32 amino acid sequences from exons 6, 7, and 10 of the common variant, as well as two versions of the common variant which differed by a G to C nonsynonymous single nucleotide polymorphism resulting in a change from glycine to alanine. These two recombinant common variant isoforms correspond to the reported sequences of two of the annexin 8 loci affected by copy number variation. Thus reactions to either, but not both, might indicate disparities in annexin 8 copy number between recipient and donor. Of 187 patients, 22 had significant antibody reactions (defined as greater than 1 standard deviation above the mean in normal controls) to either of the common variant isoforms but only 4 had reactions to both isoforms suggesting that antibodies were differentially recognizing annexin 8 isoforms based on a single nonsynonymous single nucleotide polymorphism. Six of 187 patients had significant antibody reactions against the splice variant isoform alone, suggesting that the alternatively inserted exon may be the antibody target. Taken together, our findings suggest that annexin 8 may be a target of the post-transplant humoral response due to immune disparities between recipient and donor caused by copy number variation as well as alternative splicing.

Identification of Novel Germline and Tumor-Specific Nucleotide Variants and Copy Number Variation in Clival Chordomas by Exome Sequencing

2015 ◽  
Vol 76 (S 01) ◽  
Author(s):  
Georgios Zenonos ◽  
Peter Howard ◽  
Maureen Lyons-Weiler ◽  
Wang Eric ◽  
William LaFambroise ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Exome Sequencing ◽  
Copy Number ◽  
Number Variation ◽  
Specific Nucleotide

The impact of paralog genes: detection of copy number variation in spinal muscle atrophy patients

BIOCELL ◽  
2018 ◽  
Vol 42 (3) ◽  
pp. 87-91 ◽  
Author(s):  
Sergio LAURITO ◽  
Juan A. CUETO ◽  
Jimena PEREZ ◽  
Mar韆 ROQU�
Keyword(s):  
Copy Number Variation ◽  
Muscle Atrophy ◽  
Copy Number ◽  
Number Variation ◽  
The Impact
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