Abstract
Carcinogenesis is accompanied by widespread DNA methylation changes within the cell. These changes are characterized by a globally hypomethylated genome with focal hypermethylation of numerous 5’-cytosine-phosphate-guanine-3’ (CpG) islands, often spanning gene promoters and first exons. Many of these epigenetic changes occur early in tumorigenesis and are highly pervasive across a tumor type. This allows DNA methylation cancer biomarkers to be suitable for early detection and also to have utility across a range of areas relevant to cancer detection and treatment. Such tests are also simple in construction, as only one or a few loci need to be targeted for good test coverage. These properties make cancer-associated DNA methylation changes very attractive for development of cancer biomarker tests with substantive clinical utility. Across the patient journey from initial detection, to treatment and then monitoring, there are several points where DNA methylation assays can inform clinical practice. Assays on surgically removed tumor tissue are useful to determine indicators of treatment resistance, prognostication of outcome, or to molecularly characterize, classify, and determine the tissue of origin of a tumor. Cancer-associated DNA methylation changes can also be detected with accuracy in the cell-free DNA present in blood, stool, urine, and other biosamples. Such tests hold great promise for the development of simple, economical, and highly specific cancer detection tests suitable for population-wide screening, with several successfully translated examples already. The ability of circulating tumor DNA liquid biopsy assays to monitor cancer in situ also allows for the ability to monitor response to therapy, to detect minimal residual disease and as an early biomarker for cancer recurrence. This review will summarize existing DNA methylation cancer biomarkers used in clinical practice across the application domains above, discuss what makes a suitable DNA methylation cancer biomarker, and identify barriers to translation. We discuss technical factors such as the analytical performance and product-market fit, factors that contribute to successful downstream investment, including geography, and how this impacts intellectual property, regulatory hurdles, and the future of the marketplace and healthcare system.
Highlights
Cancer is defined by extensive genetic changes and associated dysregulation in gene function and activity (Nakagawa and Fujita, 2018)
According to unpublished material released by the company, the urine sample (~5 ml) is first mixed in a 1:3 ratio with a stabilization buffer prior to shipment to their clinical lab where DNA is harvested from centrifuged cell pellets, digested with methylation-sensitive restriction enzymes, amplified with quantitative PCR (qPCR)
Results are summarized as three calls: negative, high-risk, or positive. This lab-developed test (LDT) currently targets the bladder cancer recurrence market, but promotional materials raise the possibility of early detection due to the high reported positive predictive value (PPV) and negative predictive value (NPV) of the test (89% and 92%, respectively)
Summary
Cancer is defined by extensive genetic changes and associated dysregulation in gene function and activity (Nakagawa and Fujita, 2018). Early market offerings in the DNA methylation oncology diagnostic space were based upon detecting hypermethylated DNA using fresh tumor biopsies or fixed tissue blocks in glioblastoma, prostate, and colorectal cancer (CRC) (e.g. MGMT, GSTP1, and MLH1 based assays) (Esteller et al, 1998; Herman et al, 1998; Esteller et al, 2000).
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