Researchers at the Dana-Farber Cancer Institute and other cancer research institutions have
begun developing a new blood test that is capable of screening for various types of cancer with high rates of accuracy. Investigators reported their results at the European Society for Medical Oncology (ESMO) 2019 Congress in September.

The test was created by GRAIL, Inc and uses a sequencing technology to probe the DNA for
chemical tags, called methylation, that determine if a gene is active or inactive. The test looks for DNA that cancer cells have shed into the bloodstream after they die. This is different to “liquid biopsies” which detect genetic mutations or other cancer-related changes in the DNA. The new test focuses on DNA modifications in methyl groups, which are chemical units that can be attached to DNA and control which genes are turned on or off. When methylation patterns are abnormal, it’s more likely that cancer in present.

In the study, investigators analyzed DNA that had once been inside cells but had since entered the bloodstream. In the trial, the test was used on approximately 3,600 blood samples from healthy patients and patients diagnosed with cancer. The samples came from patients with more than 20 types of cancer including colorectal, esophageal, gallbladder, lung, ovarian and pancreatic. The test was able to detect a cancer signal from blood samples that came from cancer patients and also identified where the cancer originated in the body.

The trial results were 99.4% correct, meaning the results incorrectly found that cancer was
present less than 1% of the time. Investigators pre-specified a set of cancers with high mortality rates and found that the test was also able to correctly identify these cancers. The test was better able to identify the cancers at later stages with its ability to detect cancer as follows: 32% of stage I cancers, 76% of stage II cancers, 85% of stage III cancers and 93% of stage IV cancers. The test was also able to return a result regarding the tissue of origin for 97% of the samples and correctly identified the location in 89% of cases.

While further development of the test is needed to improve its ability to detect early-stage
cancers, most cancer patients whose cancer is caught at an earlier stage have augmented
chances of long-term survival.

A group of scientists from the Dana-Farber Cancer Institute, Massachusetts General Hospital, the Broad Institute of MIT and Harvard and the Ludwig Center at Harvard Medical School studied drug-resistant gastrointestinal stromal tumors (GISTs) to increase their understanding of what causes drug resistance in these tumors. Currently, most GISTs — a type of soft-tissue cancer — are caused by gene mutations that can be targeted with drugs, however, 10% to 20% of GISTs aren’t treatable with current medications.

In the study, investigators showed that changes in how genes are read by tumor cells, but aren’t caused by genetic mutations, can still lead to the development of GIST. Their findings have also indicated further areas of study that could make it possible to stop the development of tumors and treat these drug-resistant GISTs.

In order for a person’s DNA to fit inside their cells, it must wrap itself into loops with points called insulators. Researchers found that one of the insulators that prevents a cancer-causing gene known as FGF4 (fibroblast growth factor 4) is important to understanding drug-resistant GISTs. Another part of DNA has a switch that turns the FGF4 gene on and off. In healthy cells, FGF4 and the on/off switch are on separate loops. But in some forms of GIST, the insulator doesn’t work properly, allowing the loops to merge and turn on the cancer-causing FGF4 gene.

In this study, researchers worked with a form of GIST that had lost the function of the SDH enzyme complex, a key part in creating energy in a cell. These tumors also had an increased rate of DNA methylation, a process that adds chemical “tags” to DNA. The team found that too much DNA methylation destroys insulators in cells, leading to contact between on-switches and oncogenes, including the FGF4 gene and the KIT gene. The KIT gene is usually active in other forms of GIST.

To test their findings, investigators transplanted a human GIST into a mouse and showed that the model maintained the epigenetics of the parent tumor, including increased rates of DNA methylation and defective insulators. They also showed that tumor growth could be suppressed with fibroblast growth factor receptor FGF receptor inhibitors, both alone and with enzyme-inhibiting targeted therapy.

While targeted therapies can help SDH-deficient GIST patients, they typically become resistant to standard targeted therapies quickly. Researchers hope that these findings can open avenues for testing new therapies or repurposing old ones.