Aberrant DNMT3B7 expression correlates to tissue type, stage, and survival across cancers

Abstract

Cancer cells are known for aberrant methylation patterns leading to altered gene expression and tumor progression. DNA methyltransferases (DNMTs) are responsible for regulating DNA methylation in normal cells. However, many aberrant versions of DNMTs have been identified to date and their role in cancer continues to be elucidated. It has been previously shown that an aberrant version of a de novo methylase, DNMT3B7, is expressed in many cancer cell lines and has a functional role in the progression of breast cancer, neuroblastoma, and lymphoma. It is clear that DNMT3B7 is important to tumor development in vitro and in vivo, but it is unknown if expression of the transcript in all of these cell lines translates to relevant clinical results. In this study, a bioinformatics approach was utilized to test the hypothesis that DNMT3B7 expression corresponds to tumor progression in patient samples across cancer types. Gene expression and clinical data were obtained from the Genomic Data Commons for the 33 cancer types available and analyzed for DNMT3B7 expression with relation to tissue type in matched and unmatched samples, staging of tumors, and patient survival. Here we present the results of this analysis indicating a role for DNMT3B7 in tumor progression of many additional cancer types. Based on these data, future in vitro and in vivo studies can be prioritized to examine DNMT3B7 in cancer and, hopefully, develop novel therapeutics to target this aberrant transcript across multiple tumor types.

Fig 1. Expression of DNMT3B7 in normal and tumor patient samples.

Representative graphs of 6 different tumor samples showing relative DNMT3B7 expression, as measured by reads per kilobase per million (RPKM) or RNA-Seq by Expectation Maximization (RSEM), in unmatched normal and tumor tissues in (A) HNSC, (B) UCEC, and (C) THCA. Expression of DNMT3B7 in matched patient samples is shown in (D) LIHC and (E) LUAD. DNMT3B7 expression in primary and recurrent tissues in (F) LGG (p = 0.005) was assessed when normal samples were not available. All samples shown here were significant, p < 0.001, unless otherwise stated.

Fig 2. Relative DNMT3B7 expression correlates to clinical staging.

DNMT3B7 expression was compared to clinical stage and shown to be significantly different in (A) ESCA, p = 0.012; (B) KIRC, p = 0.010; (C) KIRP, p = 0.02; (D) LUSC, p = 0.003; (E) TGCT, p<0.001; and (F) LAML, p<0.001. For (E) TGCT, there were no patient samples with a stage IV diagnosis. (F) LAML staging was measured using the French-American-British (FAB) classifications.

Fig 3. Patients with high levels of DNMT3B7 expression have lower survival rates than those with low expression levels.

The median DNMT3B7 expression for each individual tumor was determined to divide patients with that tumor into “high” (gray, dotted line) and “low” (black, solid line) expression groups. Kaplan-Meier curves were generated and statistical significance was determined for (A) CESC, p = 0.025; (B) KIRC, p = 0.009; (C) LAML, p = 0.035; (D) MESO, p = 0.013; (E) SARC, p = 0.003; and (F) SKCM, p = 0.003.