<p>PDF file - 38KB, Chromosomal Instability. Analysis testing for potential confounding of pathologic stage and tissue type on chromosomal instability. Figure S6: Fraction of genome altered (FGA, 1) in both cohorts.</p>
Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) is a poorly characterized entity among overlap myeloid syndromes. Recent studies have shown heterogeneous mutational profiles in this group being able to subclassify them into entities closely related to the more well-established disorders under the umbrella term of the MDS/MPN group. Recurrent cytogenetic alterations are, nonetheless, rare in MDS/MPN-U. Here, for the first time, we report a case of MDS/MPN-U with a t(X;17)(q28;q21) chromosomal rearrangement leading to the KANSL1-MTCP1 fusion gene.
4569 Background: Limited information exists regarding the changes that occur in UC tumors that ultimately metastasize, the lethal phenotype of UC. Recurrent copy number alterations (CNAs) have been previously identified in UC, but correlation with clinical outcomes has not been reported in metastatic UC. Methods: We identified a cohort of 94 UC patients uniformly-treated for distant metastases (platinum-based combination chemotherapy), with clinical annotatation and FFPE primary tumor tissue available. Overall survival (OS) was defined as the time from start of chemotherapy for metastatic disease to death or last follow-up. Tumor bearing areas were evaluated by a single pathologist, and genomic DNA was extracted and analyzed for copy number alterations using Agilent 4x180k high resolution comparative genomic hybridization (CGH) arrays (average resolution of 13kb). Gain and Loss Analysis of DNA (GLAD) was used to segment the array output, and Genomic Identification of Significant Targets in Cancer (GISTIC) v2 was used to assess the significance of gains/losses (log base 2 ratio > 0.9 and < -1.3, respectively). False discovery rates < 0.2 were considered significant to correct for multiple comparisons. A Cox model for survival controlling for known prognostic variables (PS and visceral metastasis) was used for analysis. Bootstrapping (500 re-samples) assessed the variability and bias of parameters as internal validation. Results: In the 94 patients (46 deaths) median OS was 15 months. 15 patients were noted to have copy number gain (CNG) of a 150 kb region of 1q23.3. These patients had a median OS of 7.3 months, compared to patients without CNG with a median OS of 18 months. Gain of 1q23.3 is significantly associated with lethal UC (adjusted HR 2.94, 95% CI 1.35-6.44, p=0.007, FDR=0.12) (Table). This finding was internally validated (HR=3.2, 95% CI 1.25-7.2). Conclusions: Genomic gain of a short segment of chromosome 1q23.3 is associated with a lethal phenotype of UC in patients with metastatic disease. External validation in an additional cohort is underway. HR (95% CI) P value 1q23.3 gain (yes vs. no) 2.94 (1.35, 6.44) 0.007 ECOG PS (1,2 vs. 0) 1.93 (1.00, 3.79) 0.05 Visceral disease (yes vs. no) 2.40 (1.25, 4.47) 0.008
562 Background: Next generation sequencing (NGS)-based molecular profiling has been widely used across various tumor types including genitourinary malignancies to better understand and potentially predict tumor behavior. The goal of this study was to determine the feasibility of using NGS to characterize mUC and to identify potentially actionable variants. Methods: Patients with locally advanced or metastatic urothelial carcinoma (mUC) treated at the Princess Margaret Cancer Center were prospectively recruited for the OCTANE study, which collects archival tumor samples to provide genomic characterization through NGS with a custom hybridization capture DNA-based panel (555 genes) or a targeted DNA/RNA amplicon panel (Oncomine Comprehensive Assay v3, 161 driver gene panel). Variants were annotated using a somatic variant scheme [PMID: 25880439] or the oncoKB database. Comprehensive clinical information including patient, disease and treatment characteristics was collected using electronic patient records. Kaplan-Meier and cox regression were used for survival analysis. Results: Of the 73 patients, median age was 65 (23-83), majority were men (69%), most had lower tract disease (80%) and 41% had de novo metastatic disease. NGS was deemed feasible, based on availability of tumor samples, and performed in 67 (92%) patients. Overall, 61 (91%) had at least one oncogenic variant, including 34 (56%) with a potentially "druggable" target. The most frequent genomic alterations found were TP53 (44%), FGFR (18%), TERT (18%), ARID1A (18%) and PIK3CA (16%), all classified as "pathogenic/likely pathogenic". Only 2 patients received targeted treatment, one as part of clinical trial and one as standard of care. mOS was numerically longer among patients with genomic mutations compared to the ones without: 55 vs 31 months (HR: 0.87, CI 95% 0.3-2.4; p:0.7). No specific mutation was shown to significantly impact survival (table). Conclusions: Use of NGS technology in characterizing the genomic profile of patients with locally advanced or metastatic UC was feasible in most cases. Oncogenic variants were detected in the majority of patients, and more than half of them harbored a potentially "druggable" target, which may lead to future therapeutic advances.[Table: see text]
Gleason scores (GS) 3+3 and 3+4 prostate cancers (PCa) differ greatly in their clinical courses, with Gleason pattern (GP) 4 representing a major independent risk factor for cancer progression. However, Gleason grade is not reliably ascertained by diagnostic biopsy, largely due to sampling inadequacies, subjectivity in the Gleason grading procedure, and a lack of more objective biomarker assays to stratify prostate cancer aggressiveness. In most aggressive cancer types, the tumor microenvironment exhibits a reciprocal pro-tumorigenic metabolic phenotype consistent with the reverse Warburg effect (RWE). The RWE can be viewed as a physiologic response to the epithelial phenotype that is independent of both the epithelial genotype and of direct tumor sampling. We hypothesize that differential expression of RWE-associated genes can be used to classify Gleason pattern, distinguishing GP3 from GP4 PCa foci. Gene expression profiling was conducted on RNA extracted from laser-capture microdissected stromal tissue surrounding 20 GP3 and 21 GP4 cancer foci from PCa patients with GS 3+3 and GS ≥4+3, respectively. Genes were probed using a 102-gene NanoString probe set targeted towards biological processes associated with the RWE. Differentially expressed genes were identified from normalized data by univariate analysis. A top-scoring pair (TSP) analysis was completed on raw gene expression values. Genes were analyzed for enriched Gene Ontology (GO) biological processes and protein-protein interactions using STRING and GeneMANIA. Univariate analysis identified nine genes (FOXO1 (AUC: 0.884), GPD2, SPARC, HK2, COL1A2, ALDOA, MCT4, NRF2, and ATG5) that were differentially expressed between GP3 and GP4 stroma (p<0.05). However, following correction for false discovery, only FOXO1 retained statistical significance at q<0.05. The TSP analysis identified a significant gene pair, namely ATG5/GLUT1. Greater expression of ATG5 relative to GLUT1 correctly classified 77.4 % of GP3/GP4 samples. Enrichment for GO-biological processes revealed that catabolic glucose processes and oxidative stress response pathways were strongly associated with GP3 foci but not GP4. FOXO1 was identified as being a primary nodal protein. We report that RWE-associated genes can be used to distinguish between GP3 and GP4 prostate cancers. Moreover, we find that the RWE response is downregulated in the stroma surrounding GP4, possibly via modulation of FOXO1.
