Common Gene Deletions Research Articles

Gene Deletions and Prognostic Values in B-Linage Acute Lymphoblastic Leukemia.

Although pediatric-like treatment regimen has remarkably improved the survival rates of adults with acute lymphoblastic leukemia (ALL), the outcome of some adult patients is still poor owing to adverse genetic features. These molecular abnormalities, especially gene deletions, may be considered for the prognosis assessment for adult patients with ALL. In this study, using multiplex ligation-dependent probe amplification (MLPA) method, gene deletions were analyzed in from 211 adult B-ALL patients treated in our center. The data showed that 68.2% (144/211) adult B-ALL patients carried gene deletions, and the frequency is much higher in Ph+B-ALL patients. IKZF1 gene deletion is the most common gene deletion in adult B-ALL, followed by CDKN2A/B deletion. In Ph-B-ALL patients, the overall survival of patients with gene deletions is inferior to that of patients without any gene deletions. More obviously, patients with IKZF1 or CDKN2A/B deletion had a worse prognosis, whereas, allogeneic hematopoietic stem cell transplantation could improve OS in patients with IKZF1 deletion, but not in patients with CDKN2A/B deletion. Moreover, the outcome of Ph-B-ALL patients with double deletion of IKZF1and CDKN2A/B may be much worse than that of patients with IKZF1 or CDKN2A/B alone. Minimal residual disease (MRD) was also analyzed together with gene deletions and demonstrated that gene deletions have a negative impact on survival only in MRD positive Ph-B-ALL patients. In conclusion, gene deletions are closely related with the prognosis of adult Ph-B-ALL patients.

Abstract LB-A18: The frequent tumor deletion of MTAP is a newly recognized potent immune checkpoint that is effectively reversed by a human methylthioadenosine degrading drug candidate

Abstract Our lab has obtained strong in vivo evidence from multiple murine tumor models that the production of methylthioadenosine (MTA) by methylthioadenosine phosphorylase (MTAP) deficient tumors potently attenuates anti-tumor immune responses, validating its role as a potent immunosuppressive molecule. We demonstrate that administration of an engineered human MTA degrading enzyme therapeutic reverses the deleterious effects of MTA on lymphocytes in vitro, and in vivo drastically impedes the growth of MTAP deficient tumors including MTAP-/- leukemia (L1210), MTAP low colon carcinoma (CT26) and an engineered MTAP-/- B16-F10 melanoma. As a single agent our therapeutic candidate elicits a large fraction of complete and durable responses in animals with established tumors, correlating with significant increases in the populations of effector T cells in both the tumor and tumor draining lymph node. We also note that enzyme treatment displays synergism in combination with existing immune checkpoint inhibitors. Despite the remarkable success of immune checkpoint inhibitors such as anti-PD1 and anti-CTLA-4 antibodies, a large fraction of tumors do not respond to immunotherapy due to additional suppressive mechanisms such as adenosinergic signaling. Approximately 15% of all cancers exhibit homozygous MTAP deletions resulting in accumulation and secretion of the adenosine (ADO) analog, MTA. Patients with cancer MTAP deletions show reduced tumor infiltrating lymphocytes (TILs) and poor overall survival in multiple tumor types. Recent work has even suggested that MTAP loss may confer resistance to antibody immune checkpoint inhibitors. Although MTA is reported to be an ADO receptor agonist, purinergic signaling alone does not explain the distinct immune suppression associated with increased MTA. In vitro, MTA (but not ADO) strongly inhibits the proliferation and viability of both CD4+ and especially CD8+ murine T cells. Similarly, treatment with ADO receptor antagonists does not restore proliferation or reverse the cytotoxicity of MTA. Only exogenous administration of MTA degrading enzymes was able to reverse these effects, indicating that MTA impacts the viability and proliferation of T cells by a mechanism independent of ADO receptor signaling. Quantitative proteomic data suggests instead that MTA acts, at least in part, via the inhibition of methyltransferases, chromatin remodeling and upregulation of P53/apoptotic pathways in lymphocytes. Collectively our data suggest that enzymatic depletion of MTA represents a unique opportunity for a biomarker driven (namely, tumor MTAP status) immunotherapeutic modality. The evidence that the consequence of MTAP deletion acts to suppress immune effector cells and promote tumor tolerance through the buildup of MTA now suggests a clear mechanism for why this is one of the more common gene deletions observed in cancer. Citation Format: Donjeta Gjuka, George Georgiou, Everett M Stone. The frequent tumor deletion of MTAP is a newly recognized potent immune checkpoint that is effectively reversed by a human methylthioadenosine degrading drug candidate [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A18. doi:10.1158/1535-7163.TARG-19-LB-A18

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.

Copy number variation and antigenic repertoire

The success of bone marrow transplantation depends on whether transplanted immune cells respond in graft versus host disease. A new study identifies a common gene deletion that is associated with immune response following transplantation.

Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4-4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.

Common Gene Deletions and Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation.

Graft-versus-host disease (GVHD) is a serious and common complication of allogeneic hematopoetic stem cell transplantation (HSCT). GVHD results from genetic incompatibilities between donor and host. Although matching of donor and recipient human leukocyte antigens (HLA) is critical to transplant outcomes, GVHD is common even in transplants involving HLA-identical sibling donors. The additional determinants of graft compatibility are poorly understood, though a small number of minor histocompatibility antigens have been reported. The human genome has recently been found to show large-scale structural variation, including large gene deletions sufficiently common to appear as homozygous gene deletions in many patients. We investigated whether donor-recipient disparity for common gene deletion polymorphisms (homozygous gene deletion in donor but not in recipient) was associated with GVHD following allogeneic HSCT in 821 HLA-identical sibling donor-recipient pairs. Patient samples and clinical outcomes data were assembled collaboratively from institutions in Finland and North America, in strict compliance with ethical standards and IRB-approved protocols. Donors and patients were typed for the presence of six common gene deletions using real-time PCR. Donor-recipient disparities were then assessed for association with acute and chronic GVHD. Donor-recipient disparities in the expected direction (-/- in donor, +/- or +/+ in recipient) for two common gene deletions, UGT2B28 and UGT2B17, were associated with chronic GVHD (OR > 4, P=0.001; and OR=2.0, P=0.05 respectively). Donor-recipient disparity for UGT2B17 was also associated with acute GVHD (OR=2.0, P=0.05). In the cohorts assembled for this study, we also observed an expected robust association for sex mismatch with chronic GVHD (OR=1.6, p=0.001) and a non-significant trend toward association with acute GVHD (OR=1.1, p=0.30). No significant association with acute or chronic GVHD was observed for the other four common gene deletion polymorphisms (GSTT1, GSTM1, OR51A2, and LCE3C). Consistent with prior studies of minor histocompatibility antigens on the Y-chromosome, we observed evidence of serologic immunoreactivity to a nine residue peptide on UGT2B17 in an HSCT recipient with mismatch at this locus. Because disparities for UGT2B17 and UGT2B28 occur in fewer than 6% of sibling-donor transplants in populations with European ancestry, they can explain only a fraction of the genetically attributable risk of GVHD. Of note, deletion of UGT2B28 appears to be more common in individuals with African and Latin American ancestry (allele frequency of 25–35%), and therefore merits investigation as a potential contributor to transplant outcome in those populations. We conclude that variation in genome structure associates with graft-versus-host disease and merits further investigation as a cause of minor histocompatibility barriers to hematopoietic stem cell transplantation. For the Transplant Structural Genetics Consortium: David Altshuler, Shannon Chilewski, Steven McCarroll (Broad Institute of Harvard and MIT, Cambridge, MA); Joseph Antin, James Bradner, Stephanie Lee, Jerome Ritz, Robert Soiffer (Dana-Farber Cancer Institute, Boston, MA); Aarno Palotie (Finnish Genome Center, Helsinki, Finland); Jukka Partanen, Hannu Turpeinen (Finnish Red Cross, Helsinki, Finland); Tapani Ruutu, Liisa Volin (Helsinki University Central Hospital, Helsinki, Finland); David Ginsburg, David Siemeniak (University of Michigan, Ann Arbor, MI).