An Animal Model of the Childhood Lymphoma Implicates Important Prognostic Genes in Cancer Survival
Loading...
Date
2018-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
Background: In the US, cancer is 2nd leading cause of death in children. Surprisingly, the prevailing treatment regimens have been modified from adult therapies. Yet, substantial differences exist between adult and pediatric cancers. Determining the underlying genetic causes of pediatric cancers is problematic for many reasons, including the overall rarity. In order to gain tractability in this disease, we need a new model that closely recapitulates pediatric cancers, but at much higher incidence. The pet dog is ideally suited to be this model. Significance: Children experience varying degrees of suffering due to the side effects of treatment modalities that are primarily non-specific. Isolating genetic causes would allow for personalized treatments and increase survival.
Purpose: The purpose of this work was to identify genetic and epigenetic (DNA methylation) biomarkers in an animal model of pediatric lymphoma that are associated cancer survival. Conceptual Framework: We used the genetic single gene-two hit model (Hussian, 2015) to guide this work. This framework combines rare and common variant theories with the addition of mutator/anti-mutator modulation to lead to disease development. Methods: Using chemotherapy naive tumor samples from 71 dogs diagnosed with aggressive lymphomas, we analyzed gene expression using Affymetrix Genechip 2.0 arrays. Additionally, we performed whole genome methylation analysis (MeDIP) on a subset of 6 dogs. Data was normalized and analyzed using a genomics statistical suite (JMP). We further validated our expression results in an online publically available database of 91 pediatric lymphoma tumors.
Results: After selecting the significant transcripts (fold-change ≥ 3 and p ≤ 0.001), we correlated these in a subset of dogs with survival time. We identified 6 prognostic genes significantly associated with cancer survival. In the methylation analysis, we identified 633 differentially methylated first exons of genes (p ≤ 0.01). Overlapping both the expression and methylation analysis, we identified 1 gene (Cadherin 1, CDH1). The expression of this gene was significantly associated with survival in pediatric lymphoma (p = 0.013). Conclusions: This study is one of the first to provide genetic understanding of aggressive lymphomas that have relevance in children. Focusing on the molecular properties of pediatric cancer will provide significant clinical utility.
Description
Keywords
Cancer, Genetics, Dog model, Pediatric lymphoma