Abstract A62: Clinical translation of liquid biopsy DNA methylation biomarkers: Lessons from two systematic reviews
Authors: Lommen Kim , Feng Zheng , Oberije Cary J.G. , van de Wetering Alouisa J. P. , Odeh Selena , Koch Alexander , Aarts Maureen J. B. , van Roermund Joep G. , Schouten Leo J. , Oosterwijk Egbert , Vaes Nathalie , Masclee Ad A. M. , Carvalho Beatriz , Meijer Gerrit A. , Zeegers Maurice P. , Herman James G. , Tjan-Heijnen Vivianne C. , Melotte Veerle , van Engeland Manon , Smits Kim 
Published: June 2020

Abstract
Background: Very few (&lt;0.1%) of DNA methylation biomarkers are eventually translated into clinical practice, even though over 5,000 have been published over the last decades. In an attempt to create an overview of the current evidence on these markers, we performed two systematic reviews on diagnostic DNA methylation biomarkers in liquid biopsies, for colorectal cancer (CRC) and renal cell carcinoma (RCC) (1). Here, we present the evidence of these systematic reviews and provide novel recommendations to improve the current clinical translation of DNA methylation biomarkers.
Methods: For CRC, we identified 109 bodily fluid biomarker studies published before January 2019 in PubMed, Embase, Cochrane Library, or Google Scholar. For RCC, we identified 6 liquid biopsy studies up to January 2019 in these databases. Data extraction (study design, patient characteristics, disease stage, tumor location, technical assays, diagnostic measures) was performed on published reports. STARD criteria and Level of Evidence (LoE) were registered to assess reporting quality and strength for clinical translation, and forest plots were generated to summarize diagnostic performance of the biomarkers.
Findings: Our systematic literature search revealed multiple issues that hamper the development of DNA methylation biomarkers for RCC and CRC diagnosis, including methodologic and technical heterogeneity and lack of validation or clinical translation. Among the most important issues were a lack of translation from tissue into liquid biopsy; for CRC 88/389 (23%) CRC markers were studied in liquid biopsies, and for RCC these numbers were 15/44 (34%). In addition, results showed a lack of independent validation, with 37/88 (42%) CRC markers and 9/15 (60%) RCC markers in liquid biopsies studied in more than one study or study population. Also, inappropriate marker identification and primer design, lack of true clinical need definition, and low reporting quality were issues that were recognized in our systematic literature searches. These issues all hamper the development of the field, keep the LoE low, and hinder the translation of DNA methylation biomarkers into clinical tests.
Interpretation: Our systematic literature searches revealed that major requirements to develop clinically relevant diagnostic DNA methylation markers are often lacking. To avoid the resulting research waste, clinical needs, intended biomarker use, and independent validation should be better considered prior to study design. In addition, improved reporting quality would facilitate meta-analysis, thereby increasing LoE and enabling clinical translation.
Reference: 1. Lommen et al. Eur Urol Oncol 2019; https://doi.org/10.1016/j.euo.2019.07.011.
Citation Format: Kim Lommen, Zheng Feng, Cary J.G. Oberije, Alouisa J. P. van de Wetering, Selena Odeh, Alexander Koch, Maureen J. B. Aarts, Joep G. van Roermund, Leo J. Schouten, Egbert Oosterwijk, Nathalie Vaes, Ad A. M. Masclee, Beatriz Carvalho, Gerrit A. Meijer, Maurice P. Zeegers, James G. Herman, Vivianne C. Tjan-Heijnen, Veerle Melotte, Manon van Engeland, Kim Smits. Clinical translation of liquid biopsy DNA methylation biomarkers: Lessons from two systematic reviews [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 A62.