Abstract B67: Genome-wide 5-hydroxymethylcytosine mapping in circulating cell-free DNA reveals prognostic implications in pancreatic ductal adenocarcinoma
Authors: Zhou Zhang, Lei You, Xingyu Lu, Yanqun Song, Chang Zeng, Rudy Chiu, Wenhui Lou, Chuan He, Yupei Zhao
Journal: Clinical Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is only the 11th most common cancer globally, but PDAC comprises a disproportionate number of total cancer deaths, ranking 7th worldwide for cancer mortality with over 400,000 annual deaths. Although advances in cancer research and clinical oncology have significantly improved patient outcomes for many human cancers, the prognosis of PDAC remains dismal with a ~5% survival rate five years after diagnosis. Precise prognosis for PDAC will likely improve clinical outcomes, e.g., through evidence-based selection of the best treatment options. Our team demonstrated the diagnostic value of 5-hydroxymethylcytosines (5hmC), a novel epigenetic marker that has been implicated in cancer pathobiology, in circulating cell-free DNA (cfDNA) for PDAC (Zhang et al., 2019 AACR Annual Meeting). In this study, we sought to explore the prognostic implications of 5hmC in cfDNA for PDAC as a minimally invasive approach. Specifically, we prospectively recruited 56 patients with PDAC (age: 60.91 ± 9.68; males: 50%) from Peking Union Medical College Hospital. We excluded patients treated with chemotherapy, radiation therapy, or immunotherapy and obtained baseline clinical, laboratory, and treatment data. Tumor staging was based on the Cancer Staging Manual (8th edition) from the American Joint Committee on Cancer. We performed genome-wide 5hmC mapping in patient-derived cfDNA using the 5hmC-Seal technique, a highly sensitive method requiring &amp;lt; 5 mL of plasma. We evaluated the potential prognostic value of the 5hmC in cfDNA for predicting overall survival (all-cause mortality) within 36 months after surgery. We detected a panel of 12 marker genes using the elastic net regularization on the Cox proportional hazards model and developed a weighted prognostic score. The 5hmC-based prognostic scores separated patients by their overall survival (Hazard Ratio: 11.19, 95% Confidence Interval: 3.72-33.62, log-rank p &amp;lt; 0.0001) after surgery. We further showed that the 5hmC-based prognostic scores demonstrated a superior capability for predicting patients’ overall survival compared to existing clinical prognostic factors, such as tumor stage and CA19-9 levels. Exploring these prognostic genes using the Human Pathology Atlas for PDAC patients showed that several genes were significantly associated with the five-year survival for PDAC patients from The Cancer Genome Atlas (log-rank p &amp;lt; 0.001), including SEPHS1 (encoding selenophosphate synthetase 1), PFDN5 (encoding prefoldin subunit 5), and MTERF4 (Mitochondrial transcription termination factor 4). Though limited by the relatively short follow-up time in this study, our exploration suggested that the 5hmC profiles of a 12-gene prognostic panel in cfDNA could help differentiate patients with PDAC by their overall survival after surgery. More comprehensive follow-up investigations will ultimately establish the prognostic utility of this noninvasive approach for precision care of PDAC in the clinic. Citation Format: Zhou Zhang, Lei You, Xingyu Lu, Yanqun Song, Chang Zeng, Rudy Chiu, Wenhui Lou, Chuan He, Yupei Zhao. Genome-wide 5-hydroxymethylcytosine mapping in circulating cell-free DNA reveals prognostic implications in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B67.