A new blood test detecting methylation patterns associated with cancer in free-floating DNA in blood, being developed by GRAIL, a company combining science, technology, and population-scale clinical studies to reveal cancer at its beginnings, can detect and localize multiple types of cancer with a high degree of accuracy.
This is the conclusion drawn from study results of a multi-center trial presented by Geoffrey R. Oxnard, MD, from Dana-Farber Cancer Institute during a session at the European Society for Medical Oncology (ESMO) 2019 Congress being held in Barcelona, Spain September 27 – October 1, 2019.
The new blood test uses next-generation sequencing (NGS) also known as massively parallel, high-throughput sequencing or deep sequencing, a DNA sequencing technology which has revolutionized genomic research, to probe DNA for tiny chemical tags (methylation) that influence whether genes are active or inactive.
NGS allows for sequencing of DNA and RNA much more quickly and cheaply than the previously used Sanger sequencing, and as a result, revolutionized the study of genomics and molecular biology.
When applied to nearly 3,600 blood samples – some from patients with cancer, some from people who had not been diagnosed with cancer at the time of the blood draw – the test successfully picked up a cancer signal from the cancer patient samples, and correctly identified the tissue from where the cancer began (the tissue of origin).
The test’s specificity – its ability to return a positive result only when cancer is actually present – was high, as was its ability to pinpoint the organ or tissue of origin, researchers found.
The new test looks for DNA, which cancer cells shed into the bloodstream when they die. In contrast to “liquid biopsies,”* which detect genetic mutations or other cancer-related alterations in DNA, the technology focuses on modifications to DNA known as methyl groups.
Methyl groups are chemical units that can be attached to DNA, in a process called methylation, to control which genes are “on” and which are “off.” Abnormal patterns of methylation turn out to be, in many cases, more indicative of cancer – and cancer type – than mutations are.
The new test zeroes in on portions of the genome where abnormal methylation patterns are found in cancer cells.
“Our previous work indicated that methylation-based assays outperform traditional DNA-sequencing approaches to detecting multiple forms of cancer in blood samples,” said Oxnard, the study’s lead author.
“The results of the new study demonstrate that such assays are a feasible way of screening people for cancer,” Oxnard added.
In the study, investigators analyzed cell-free DNA (DNA that had once been confined to cells but had entered the bloodstream upon the cells’ death) in 3,583 blood samples, including 1,530 from patients diagnosed with cancer and 2,053 from people without cancer. The patient samples comprised more than 20 types of cancer, including hormone receptor-negative breast, colorectal, esophageal, gallbladder, gastric, head and neck, lung, lymphoid leukemia, multiple myeloma, ovarian, and pancreatic cancer.
The overall specificity was 99.4%, meaning only 0.6% of the results incorrectly indicated that cancer was present.
The sensitivity of the assay for detecting a pre-specified high mortality cancers (the percent of blood samples from these patients that tested positive for cancer) was 76%. Within this group, the sensitivity was 32% for patients with stage I cancer; 76% for those with stage II; 85% for stage III; and 93% for stage IV.
The study results also demonstrated sensitivity across all cancer types was 55%, with similar increases in detection by stage. For the 97% of samples that returned a tissue of origin result, the test correctly identified the organ or tissue of origin in 89% of cases.
“Detecting even a modest percent of common cancers early could translate into many patients who may be able to receive more effective treatment if the test were in wide use,” Oxnard concluded.
In their groundbreaking paper, published in 1983, Feinberg and Vogelstein were the first to associate differences in DNA methylation status to cancer.  Since the publication of this paper there has been an explosion of research regarding abnormal DNA methylation in complex diseases, including cancer. And the development of Grail’s new blood test confirms that the study of abnormal methylation patterns has, indeed, successfully entered the arena of relevant clinical applications.
* Also known as fluid biopsy or fluid phase biopsy
 Abstract LBA77. Geoffrey R. Oxnard, et al. Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA) Proffered Paper Session – Translational Research: September 28, 2019: 8:30-10:00 AM CEST, Pamplona Auditorium (Hall 2)
 Feinberg AP, Vogelstein B.Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983; 301:89–92. 10.1038/301089a0 [PubMed][Article]