Abstract
Thoracic high dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4–6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of >35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.
Highlights
For detection of cardiomyocyte-specific Cell-free DNA (cfDNA) an amplicon with 6 CpGs was analyzed. This is the first study in which a cardiomyocyte cfDNA methylation marker was used to detect cardiac damage as a result of chemotherapy and radiation treatment in cancer patients
The identification of tissue-specific, cfDNA relies on DNA methylation patterns that are highly cell-type specific
In order to detect cardiomyocyte-derived cfDNA in the circulation, we designed an amplicon sequencing method whereby first DNA was extracted from serum, DNA was bisulfite converted, the gold standard method to distinguish between methylated and non-methylated CpGs (Figure 1)
Summary
The number of patients living with cancer and cancer survivors is increasing in the United States due to advances in early detection, improved cancer treatment and the aging population [1]. Development of novel therapies, often given in sequence or concomitantly with conventional therapies, has resulted in prolonged survival and carries an increased risk of adverse events. Cardiovascular toxicities from conventional cytotoxic or pathwaytargeted therapies, immunotherapy, radiation treatment have been recognized and can include myocardial infarction, left ventricular dysfunction, hypertension, heart failure, coronary artery disease and arrhythmias [1,2]. We evaluate the use of circulating nucleic acids as a potential marker of cardiac injury related to cancer therapies and present feasibility data in esophageal cancer patients treated with chemoradiation
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