Search

PDF file - 180K, Supplemental Figure 1: Complete deletion of Dlg1 in three independent Cre-expression systems permits development of mature, peripheral B cell subsets.

Drosophila melanogaster discs large (dlg) is an essential tumor suppressor gene (TSG) controlling epithelial cell growth and polarity of the fly imaginal discs in pupal development. A mammalian ortholog, Dlg1, is involved in embryonic urogenital morphogenesis, postsynaptic densities in neurons, and immune synapses in lymphocytes. However, a potential role for Dlg1 as a mammalian TSG is unknown. Here, we present evidence that loss of Dlg1 confers strong predisposition to the development of malignancies in a murine model of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Using mice with conditionally deleted Dlg1 alleles, we identify a novel “pre-leukemic” stage of developmentally arrested early B-lineage cells marked by preeminent c-Myc expression. Mechanistically, we show that in B-lineage progenitors Dlg1 interacts with and stabilizes the PTEN protein, regulating its half-life and steady-state abundance. The loss of Dlg1 does not affect the level of PTEN mRNAs but results in a dramatic decrease in PTEN protein, leading to excessive phosphoinositide 3-kinase signaling and proliferation. Our data suggest a novel model of tumor suppression by a PDZ domain-containing polarity gene in hematopoietic cancers. Cancer Immunol Res; 1(6); 426–37. ©2013 AACR.

PDF file - 181K, Supplemental Figure 5: Histopathology analysis of lymph node and spleen of p53 KO, DKO, and B6/CTRL mice.

PDF file - 88K, Supplemental Table 1: Primers used for qRT-PCR.

PDF file - 61K, Supplemental Figure 4: Diminished expression of endogenous PTEN protein in BCR-Abl transformed Dlg1 deficient B cells.

PDF file - 81K

PDF file - 115K, Supplemental Figure 6: Chromosomal translocations visualized by Spectral Karyotyping (SKYTM) analysis of splenic tumors.

PDF file - 132K, Supplemental Figure 3: Dissemination of oncogenically- transformed pre-B cells in the in vivo model of retrovirally- induced BCR-ABL-positive B-ALL.

Background Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear. Methods We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection. Results When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A, CDKN2B, EGFR, PTEN, TERT promoter, and TP53. All patients possessed at least one of these 6 mutant genes. Conclusions This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma with much of its pathogenesis poorly understood. Mutations in the JAK/STAT pathway have been identified in a substantial proportion of cases, as well as copy number aberrations (CNAs). However, a more discrete characterization is vital to identify those with a germline predisposition to develop BIA-ALCL when exposed to a textured implant, and to identify targets for precision anti-BIA-ALCL therapeutics.To determine if there are recurrent gene mutations in BIA-ALCL patients in a cohort at a single institution.Ten patients were included that were diagnosed with BIA-ALCL between April 2015 and May 2020. Whole exome sequencing (WES) was performed on 8 tumor and normal BIA-ALCL samples and whole genome sequencing (WGS) was performed on 3 BIA-ALCL fluid samples. Samples were sequenced on an Illumina NovaSeq 6000. Data was analyzed using the Illumina DRAGEN Bio-IT Platform v3.8 workflow.This study was carried out at Barnes Jewish Hospital/Siteman Cancer Center.Patients were included if they have a pathology proven diagnosis of BIA-ALCL.Incidence and quantification of recurrent mutations in tumor samples of patients with BIA-ALCL evaluated via WES and WGS.Nearly all BIA-ALCLs showed substantial CNAs. Most patients had missense mutations in large genes with predominantly C to T transitions. Two cases had STAT3 mutations, consistent with previously reported data. Whole genome sequencing showed a critically deleted 7Mb region on chromosome 11 at 11q22.3 region in all 3 samples evaluated. This region contains the ATM gene which upon deletion in mouse models has shown an increased number of tumors. Clinically, the overall prognosis of BIA-ALCL was favorable; one patient passed from complications.There are no highly recurrent mutations in BIA-ALCL, however, 11q22.3 deletions were consistent across WGS cases and present in some exomes. Given the small sample size due to the rarity of the disease, genomic evaluation of a larger cohort is necessary to confirm this finding. Financial support for this study was provided by the Aesthetic Surgery Education Research Foundation and Barnes Hospital Foundation.