Genome-Wide 5hmC Profiling of Neuroblastoma Tumors and Patient Cell-Free DNA
Background
Neuroblastoma, a common pediatric cancer, is remarkable for its broad spectrum of clinical behavior. Although some children are highly curable, nearly half of all patients have clinically aggressive tumors.
Despite intensive therapy, the outcome remains poor for children with high-risk neuroblastoma and more effective therapies are desperately needed. To improve survival, we also need predictive, quantifiable measures (biomarkers) that will identify patients who will not respond to standard treatments and may benefit from new treatment approaches.
Project Goal
Dr. Susan Cohn, an internationally-recognized expert in neuroblastoma, and Dr. Chuan He, a renowned chemist at the University of Chicago, are partnering to evaluate a promising new biomarker, 5-hydroxymethylcytosine (5hmC). Dr. He has recently developed a highly sensitive chemical labeling technology that can be used to evaluate this biomarker in small quantities of DNA found in the blood. Preliminary studies show that 5hmC is predictive of response to treatment and outcome in adults with cancer. Although this biomarker has not been studied previously in children with cancer, we hypothesize that 5hmC profiles will serve as robust biomarkers for children with neuroblastoma and that it will be possible to comprehensively profile 5hmC using blood samples. If successful, this study will lead to the discovery of new, powerful biomarkers that can be used to monitor a patient's response to treatment and predict relapse and survival. By identifying children with high-risk neuroblastoma who are likely to relapse with standard treatment, ultimately these biomarkers could be used to individualize treatment and improve survival.
Project Update - June 2020
The outcome for patients with high-risk neuroblastoma remains dismal with less than 50% achieving long-term survival with current treatment. Thus, there is an urgent need for more effective therapies and novel prognostic factors that can be used to identify patients who will not respond to standard treatments and may benefit from alternative approaches. We used a highly sensitive and selective chemical labeling technology developed by Dr. Chuan He (co-PI; University of Chicago) that enables the detection of a mark [called 5-hydroxymethylcytosine (5hmC)] that is deposited on DNA. The pattern of deposition of the 5hmC marks varies in different types of cells, and there is increasing evidence that this mark plays an important role in regulating gene expression and cell biology. Dr. He's laboratory has demonstrated that the pattern of 5hmC marks differs in DNA isolated from common adult cancers versus benign tumors and normal tissue. More recently, he has evaluated 5hmC marks in circulating cell-free DNA (cfDNA) isolated from blood samples from adult patients with or without cancer. These studies have shown that this technology can be used to distinguish patients who have cancer versus those who are cancer-free. Although little is known about 5hmC marks in pediatric cancer, our studies show that the distribution of 5hmC marks differs on DNA isolated from aggressive neuroblastomas compared to tumors associated with a favorable outcome. Further, our preliminary results indicate that the pattern of 5hmC marks in high-risk neuroblastoma tumors is prognostic of patient survival. We are currently analyzing additional high-risk tumors, and if our results are confirmed, this biomarker may provide novel prognostic information that will enable more effective, individualized treatments and improved survival. We also hypothesize that we will be able to monitor response to therapy by comprehensively profiling 5hmC marks in cell-free DNA (cfDNA) isolated from blood samples from children with neuroblastoma collected before and after treatment. To date, we have collected 71 cfDNA samples from 32 neuroblastoma patients and 34 healthy control samples. We are in the process of analyzing the 5hmC profiles in the cfDNA collected from these patients to test this hypothesis. If successful, analyzing 5hmC marks in diagnostic tumors will lead to improved methods for predicting the survival of patients with neuroblastoma, information that physicians can use to optimized treatments and improve survival. Our studies may also lead to the discovery of novel, powerful prognostic markers that can be assayed in blood samples to monitor a patient's response to treatment. Alternative approaches could be considered for children who are not responding to standard therapy, and we envision that such individualized, biomarker-driven treatment decisions will ultimately lead to improved survival of children with high-risk neuroblastoma.
