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Gene expression signature predicts induction treatment response and clinical outcome in adult Colombian patients with B-acute lymphoblastic leukemia

ABSTRACT: Background. B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Only 61% of Colombian adult patients with ALL achieve complete remission and a median overall survival of less than 11.3 months and event-free survival of 7.34 months. Identification of prognostic factors is crucial for proper treatment strategies and optimal results of therapy. The goal of our study was to determine if gene expression signatures correlate with response to therapy and to evaluate the utility of these as prognostic tools for survival to better predict patient risk prior to therapy. Methods and findings. This study included 43 adult patients newly diagnosed with B-cell precursor or common B-ALL. Through microarray gene expression profiles, we identified 442 genes differentially expressed between 27 leukemia patients who responded or not to induction chemotherapeutic treatment. Hierarchical analysis with the 99 most differentially expressed genes between the two groups revealed 3 sets of patients that differed in their clinical characteristics, giving these genes high prognostic clinical outcome impact. We validated the expression of 7 genes by RT-PCR in 43 patients, and in addition to finding a correlation with gene expression profiles, we established correlations with good and poor prognosis from the time of diagnosis. Conclusions. Our study suggests that the response to induction treatment and clinical outcome of patients can be predicted from the onset of the disease and that gene expression profiles can be used to stratify patient risk adequately and accurately. The present study represents the first that shows that gene expression profiling could become a clinically relevant tool for stratification in the early course of disease of Colombian adults B-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76349 | GEO | 2016/04/06

SECONDARY ACCESSION(S): PRJNA306955

REPOSITORIES: GEO

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Project description:Background. B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Only 61% of Colombian adult patients with ALL achieve complete remission and a median overall survival of less than 11.3 months and event-free survival of 7.34 months. Identification of prognostic factors is crucial for proper treatment strategies and optimal results of therapy. The goal of our study was to determine if gene expression signatures correlate with response to therapy and to evaluate the utility of these as prognostic tools for survival to better predict patient risk prior to therapy. Methods and findings. This study included 43 adult patients newly diagnosed with B-cell precursor or common B-ALL. Through microarray gene expression profiles, we identified 442 genes differentially expressed between 27 leukemia patients who responded or not to induction chemotherapeutic treatment. Hierarchical analysis with the 99 most differentially expressed genes between the two groups revealed 3 sets of patients that differed in their clinical characteristics, giving these genes high prognostic clinical outcome impact. We validated the expression of 7 genes by RT-PCR in 43 patients, and in addition to finding a correlation with gene expression profiles, we established correlations with good and poor prognosis from the time of diagnosis. Conclusions. Our study suggests that the response to induction treatment and clinical outcome of patients can be predicted from the onset of the disease and that gene expression profiles can be used to stratify patient risk adequately and accurately. The present study represents the first that shows that gene expression profiling could become a clinically relevant tool for stratification in the early course of disease of Colombian adults B-ALL. Stem cells from bone marrow samples from B-acute lymphoblastic leukemia (B-ALL) patients responding or not to the inductive therapy were isolated by sorting, and the gene expression was compared between the two groups. This submission includes samples from 27 B-ALL patients and 3 healthy individuals.

Project description:A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC), comprising over 90% of all pancreatic cancers, remains a lethal disease with an estimated 232,000 new cases, 227,000 deaths per year worldwide, and a less than 5% five-year survival rate. Currently the standard of care for the 20% of patients with localized disease is surgery followed by chemotherapy, and in some cases radiation. Unfortunately despite the use of adjuvant therapy, median survival remains at best 23 months. It is important to note however, that up to 27% of patients with resected PDAC can survive for five years. However, in these studies examining actual long-term survivors, only two have found that adjuvant therapy was associated with improved survival. In addition, randomized controlled trials of gemcitabine-based chemotherapy demonstrate an improvement in median survival of at best 3 months. One possible conclusion from these studies is that tumor biology dictates outcome and that our current adjuvant therapy has only a modest impact on altering a patient's course.Hypothesizing that the dismal outcome of patients with localized disease is due to the presence of micrometastasic disease, current clinical investigation has focused on preoperative or neoadjuvant therapy. This approach, where patients who cannot tolerate the stress of therapy or develop metastatic disease during treatment are spared surgery, has demonstrated an overall survival of 34 months in this highly selected patient population. Therefore the ability to select patients who would most benefit from a neoadjuvant approach may be important. One way to do this is to define a prognostic gene signature that can identify patients with more aggressive tumor biology upfront. reference x sample The 30 Nebraska and UNC samples were not analyzed with clinical data so it is not provided. One of the PE samples is missing some clinical data.

Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.

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Gene expression signature predicts induction treatment response and clinical outcome in adult Colombian patients with B-acute lymphoblastic leukemia

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