Genome-Wide DNA Copy Number Analysis of Acute Lymphoblastic Leukemia Identifies New Genetic Markers Associated with Clinical Outcome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75671 | GEO | 2016/05/03
SECONDARY ACCESSION(S): PRJNA305049
REPOSITORIES: GEO
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Project description:UnlabelledIdentifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge.AimsTo characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL.
| S-EPMC4752220 | biostudies-literature
Project description:Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups.
| S-EPMC3280266 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a genetically highly heterogeneous disease, and numerous genetic aberrations in the leukemic genome are responsible for the biological and clinical differences among particular ALL subtypes. However, there is limited knowledge about the association of whole genome copy number abnormalities (CNAs) in childhood T-cell ALL with the course of leukemia and outcome. The aim of study was identification the pattern of whole genome CNAs in 86 newly diagnosed childhood T-ALL using a high-density single-nucleotide polymorphism (SNP) array.A series of bone marrow aspirates from 86 children with newly diagnosed T-ALL were analysed prior to any oncological treatment.
2020-03-24 | GSE147381 | GEO
Project description:Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1, PAX5, CDKN2A/B, RB1, BTG1, ETV6, and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1plus and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or L-asparaginase and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1-like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses.
| S-EPMC6420659 | biostudies-literature
Project description:We analyzed 52 Diagnostic samples from childhood Acute lymphoblastic leukemia samples
2015-08-11 | GSE69229 | GEO
Project description:Background: The occurrence of lung adenocarcinoma (LUAD) is a complicated process, involving the genetic and epigenetic changes of proto-oncogenes and oncogenes. The objective of this study was to establish new predictive signatures of lung adenocarcinoma based on copy number variation (CNVs) and gene expression data. Methods: Next-generation sequencing was implemented to obtain gene expression and CNV information. According to univariate, multivariate survival Cox regression analysis and Lasso analysis, the expression profiles of lung adenocarcinoma patients were screened and a risk score formula was established and experimentally validated in a local cohort. The model was evaluated by three independent cohorts, and then validated by clinical samples from LUAD patients. Results: A total of 844 CNV-related differential expressed genes (CNV related DEGs) were identified. An CNV associated-six gene signature was dramatically linked to overall survival in lung adenocarcinoma samples from both training and validation groups. Functional enrichment analysis further revealed involvement of genes in p53 signaling pathway and cell cycle, as well as the mismatch repair pathway. Risk score is an independent marker considering clinical parameters and had better prediction in clinical sub-population. The same signature also classified tumors tissues of clinical patients those with CNV detected from their corresponding non-tumorous tissues with an accuracy of 0.92. Conclusions: In conclusion, we identified a new class of 6 CNV-related gene markers that may act as efficient prognostic predictors of lung adenocarcinoma, thus contributing to individualized treatment decisions in patients.
2022-10-26 | GSE197346 | GEO
Project description:We analyzed 52 Diagnostic samples from childhood Acute lymphoblastic leukemia samples We compared methylation profiles with four ALL cytogentic subtypes using (n=26) long term remission vs. (n=26) that went on to relapse
2015-08-11 | E-GEOD-69229 | biostudies-arrayexpress
Project description:To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19 CD10 B-cell progenitors (n=4). Expression of 30 genes differentially expressed by > 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 105 BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.
2011-04-20 | GSE28497 | GEO
Project description:This comparative genomic hybridization (CGH) study investigated the effect of BCL6 on clonal evolution in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). The frequencies of copy number alterations in BCR-ABL1-transformed BCL6+/+ and BCL6-/- leukemias were determined.
2010-09-29 | GSE24400 | GEO
Project description:Copy number variations (CNVs) are being used as genetic markers or functional candidates in gene-mapping studies. However, unlike single nucleotide polymorphism or microsatellite genotyping techniques, most CNV detection methods are limited to detecting total copy numbers, rather than copy number in each of the two homologous chromosomes. To address this issue, we developed a statistical framework for intensity-based CNV detection platforms using family data. Our algorithm identifies CNVs for a family simultaneously, thus avoiding the generation of calls with Mendelian inconsistency while maintaining the ability to detect de novo CNVs. Applications to simulated data and real data indicate that our method significantly improves both call rates and accuracy of boundary inference, compared to existing approaches. We further illustrate the use of Mendelian inheritance to infer SNP allele compositions in each of the two homologous chromosomes in CNV regions using real data. Finally, we applied our method to a set of families genotyped using both the Illumina HumanHap550 and Affymetrix genome-wide 5.0 arrays to demonstrate its performance on both inherited and de novo CNVs. In conclusion, our method produces accurate CNV calls, gives probabilistic estimates of CNV transmission and builds a solid foundation for the development of linkage and association tests utilizing CNVs.
| S-EPMC2588508 | biostudies-other